CAL-101: A phosphatidylinositol-3-kinase p110-delta inhibitor for the treatment of lymphoid malignancies

Expert Opinion on Investigational Drugs

Volumn 21, Issue 1, 2012, Pages 15-22

  Castillo, Jorge J ^a   Furman, Michael ^b   Winer, Eric S ^c  

^a Division of Hematology/Oncology   (United States)

^b MIRIAM HOSPITAL   (United States)

^c RHODE ISLAND HOSPITAL   (United States)

Author keywords

CAL 101; Chronic lymphocytic leukemia; Lymphoma; PI3K inhibitor; Plasma cell myeloma

Indexed keywords

BENDAMUSTINE; CAL 101; FLUDARABINE PHOSPHATE; OFATUMUMAB; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN P110; RITUXIMAB; UNCLASSIFIED DRUG;

ALANINE AMINOTRANSFERASE BLOOD LEVEL; ANEMIA; APOPTOSIS; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; B CELL LYMPHOMA; CHRONIC LYMPHATIC LEUKEMIA; CONTINUOUS INFUSION; DISEASE SEVERITY; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG SAFETY; FEBRILE NEUTROPENIA; GENE DELETION; HODGKIN DISEASE; HUMAN; LYMPHATIC SYSTEM TUMOR; MAXIMUM PLASMA CONCENTRATION; MULTIPLE MYELOMA; NEUTROPENIA; NONHODGKIN LYMPHOMA; PNEUMONIA; PROTEIN LOCALIZATION; REVIEW; SIDE EFFECT; SIGNAL TRANSDUCTION; THROMBOCYTOPENIA; TREATMENT OUTCOME; TREATMENT RESPONSE;

ANTINEOPLASTIC AGENTS; DRUG EVALUATION, PRECLINICAL; HUMANS; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; LYMPHOMA; MULTIPLE MYELOMA; PHOSPHATIDYLINOSITOL 3-KINASES; PURINES; QUINAZOLINONES;

EID: 84555191770     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2012.640318     Document Type: Review

References (35)

1. Markman B, Dienstmann R, Tabernero J. Targeting the PI3K/Akt/mTOR pathway-beyond rapalogs. Oncotarget 2010;1(7):530-43
2. Reif K, Okkenhaug K, Sasaki T, et al. Cutting edge: differential roles for phosphoinositide 3-kinases, p110gamma and p110delta, in lymphocyte chemotaxis and homing. J Immunol 2004;173(4):2236-40 (Pubitemid 39063077)
3. Saudemont A, Garcon F, Yadi H, et al. p110gamma and p110delta isoforms of phosphoinositide 3-kinase differentially regulate natural killer cell migration in health and disease. Proc Natl Acad Sci USA 2009;106(14):5795-800
4. Borlado LR, Redondo C, Alvarez B, et al. Increased phosphoinositide 3-kinase activity induces a lymphoproliferative disorder and contributes to tumor generation in vivo. FASEB J 2000;14(7):895-903. (Pubitemid 30241666)
5. Chantry D, Vojtek A, Kashishian A, et al. p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J Biol Chem 1997;272(31):19236-41 (Pubitemid 27337713)
6. Vanhaesebroeck B, Welham MJ, Kotani K, et al. P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc Natl Acad Sci USA 1997;94(9):4330-5 (Pubitemid 27194241)
7. Herman SE, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood 2010;116(12):2078-88.
8. Ikeda H, Hideshima T, Fulciniti M, et al. PI3K/p110{delta} is a novel therapeutic target in multiple myeloma. Blood 2010;116(9):1460-8.
9. Uddin S, Hussain AR, Siraj AK, et al. Role of phosphatidylinositol 3'-kinase/AKT pathway in diffuse large B-cell lymphoma survival. Blood 2006;108(13):4178-86 (Pubitemid 44913290)
10. Hasselblom S, Hansson U, Olsson M, et al. High immunohistochemical expression of p-AKT predicts inferior survival in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Br J Haematol 2010;149(4):560-8
11. Rudelius M, Pittaluga S, Nishizuka S, et al. Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. Blood 2006;108(5):1668-76 (Pubitemid 44316136)
12. Garcia-Martinez JM, Wullschleger S, Preston G, et al. Effect of PI3K-and mTOR-specific inhibitors on spontaneous B-cell follicular lymphomas in PTEN/LKB1-deficient mice. Br J Cancer 2011;104(7):1116-25
13. Renne C, Willenbrock K, Martin-Subero JI, et al. High expression of several tyrosine kinases and activation of the PI3K/AKT pathway in mediastinal large B cell lymphoma reveals further similarities to Hodgkin lymphoma. Leukemia 2007;21(4):780-7 (Pubitemid 46444563)
14. Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 2011;117(2):591-4.
15. Hoellenriegel J, Meadows SA, Sivina M, et al. The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood 2011
16. Herman SE, Lapalombella R, Gordon AL, et al. The role of phosphatidylinositol 3-kinase-delta in the immunomodulatory effects of lenalidomide in chronic lymphocytic leukemia. Blood 2011;117(16):4323-7
17. Chanan-Khan A, Miller KC, Lawrence D, et al. Tumor flare reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response. Cancer 2011;117(10):2127-35
18. Meadows SA, Kashishian A, Johnson D, et al. CAL-101, a Potent selective inhibitor of the p110{delta} Isoform of Phosphatidylinositol 3-kinase, Attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. ASH Annual Meeting Abstracts 2010;116(21):3926
19. Coutre SE, Byrd JC, Furman RR, et al. Phase I study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110d, in patients with previously treated chronic lymphocytic leukemia. ASCO Meeting Abstracts 2011;29(15 Suppl):6631
20. Furman RR, Byrd JC, Brown JR, et al. CAL-101, An isoform-selective inhibitor of Phosphatidylinositol 3-Kinase P110 {delta}, demonstrates clinical activity and pharmacodynamic effects in patients with relapsed or refractory chronic lymphocytic leukemia. ASH Annual Meeting Abstracts 2010;116(21):55.
21. Kahl B, Byrd JC, Flinn IW, et al. Clinical safety and activity in a phase 1 study of CAL-101, an isoform-selective inhibitor of Phosphatidylinositol 3-Kinase P110 {delta}, in patients with relapsed or refractory Non-Hodgkin lymphoma. ASH Annual Meeting Abstracts 2010;116(21):1777.
22. Flinn IW, Schreeder MT, Coutre SE, et al. A phase I study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110 {delta}, in combination with anti-CD20 monoclonal antibody therapy and/or bendamustine in patients with previously treated B-cell malignancies. ASCO Meeting Abstracts 2011;29(15 Suppl):3064
23. Flinn IW, Schreeder MT, Wagner-Johnston N, et al. A Phase 1 study of CAL-101, An isoform-selective inhibitor of Phosphatidylinositol 3-Kinase P110{delta}, in combination with rituximab and/or bendamustine in patients with relapsed or refractory B-Cell malignancies. ASH Annual Meeting Abstracts 2010;116(21):2832
24. An Extension Study for Patients Who Are Deriving Benefit With CAL-101 to Continue on Treatment at the End of the Current Study (101-99). ClinicalTrials.gov [website] Available from: http://clinicaltrials.gov/ct2/show/ NCT01090414 [Accessed on 5 September 2011]
25. Safety and Efficacy Study of CAL-101 in Patients With Previously Untreated Low-grade Lymphoma. ClinicalTrials.gov [website] Available from: http://clinicaltrials.gov/ct2/show/NCT01306643 [Accessed on 5 September 2011]
26. Phase 2 Safety and Efficacy Study of CAL-101 (GS-1101) in Relapsed or Refractory Hodgkin Lymphoma. ClinicalTrials.gov [website] Available from: http://clinicaltrials.gov/ct2/show/NCT01393106 [Accessed on 5 Septmeber 2011]
27. Efficacy and Safety Study of CAL-101 in Patients With Indolent B-Cell Non-Hodgkin Lymphoma (DELTA). ClinicalTrials.gov [website] Available from: http://clinicaltrials.gov/ct2/show/NCT01282424 [Accessed on 5 September 2011]
28. A Study of CAL-101 and Rituximab in Elderly Patients With Untreated CLL or SLL (101-08). ClinicalTrials.gov [website] Available from: http://clinicaltrials.gov/ct2/show/NCT01203930 [Accessed on 5 September 2011]
29. Study to Investigate CAL-101 in Combination With Chemotherapeutic Agents and CD20 mAb in Patients With Relapsed or Refractory Indolent B-cell Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia. ClinicalTrials. gov [website] Available from: http://clinicaltrials.gov/ct2/show/NCT01088048 [Accessed on 5 September 2011]
30. Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 2005;23(18):4117-26 (Pubitemid 46211317)
31. Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006;7(5):379-91
32. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376(9747):1164-74
33. Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol 2010;28(30):4621-9
34. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010;11(1):29-37
35. Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 2010;363(19):1812-21