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87 Preliminary Results Of a Phase II Study Of Single Agent Bay 80-6946, a Novel PI3K Inhibitor, In Patients With Relapsed/Refractory, Indolent Or Aggressive Lymphoma  

Program: Oral and Poster Abstracts
Type: Oral
Session: 623. Lymphoma: Chemotherapy, excluding Pre-Clinical Models: Novel Agents in Lymphoma Therapy
Sunday, December 8, 2013: 5:30 PM
La Nouvelle Ballroom AB (Ernest N. Morial Convention Center)

Martin Dreyling1, Franck Morschhauser, MD, PhD2*, Dominique Bron, MD, PhD3, Krimo Bouabdallah, MD4*, Umberto Vitolo, MD5, Kim Linton6*, Eric Van Den Neste, MD, PhD7*, Silvia Mappa, MD8*, Marius Giurescu, MD, PhD9*, Barrett H. Childs, MD10 and Pier Luigi Zinzani, MD11

1Klinikum der Universität München-Campus Grosshadern, Munich, Germany
2Hopital Claude Huriez, CHRU Lille, Lille, France
3Hematology, Institut Jules Bordet, ULB, Brussels, Belgium
4Service d'Hématologie et de Thérapie Cellulaire, University Hospital of Bordeaux, Pessac, France
5Azienda Ospedaliera Città della Salute e della Scienza, Turin, Italy
6Christie Hospital, Manchester, United Kingdom
7Hematology Department, Cliniques universitaires UCL Saint-Luc, Brussels, Belgium
8Bayer S.p.A., Milan, Italy
9Bayer Pharma AG, Berlin, Germany
10Global Clinical Development, Bayer HealthCare Pharmaceuticals, Whippany, NJ
11University of Bologna, Institute of Hematology and Medical Oncology L.A. Seragnoli, Bologna, Italy

Introduction:  BAY 80–6946 is a potent and reversible Class I phosphatidylinositol-3-kinase (PI3K) inhibitor with significant activity against both PI3K-δ and PI3K-α isoforms. The PI3K-α inhibitory activity may overcome a PI3K-mediated mechanism of resistance triggered by PI3K-δ inhibition.  A phase I dose-escalation study (Patnaik et al, ASH 2012) established the maximum tolerated dose of BAY 80-6946 (0.8 mg/kg) and reported promising activity (6/6 PR) in follicular lymphoma. In the present study we further investigated the activity and safety of BAY 80-6946 in patients with indolent or aggressive lymphoma subtypes that have progressed after standard therapy.

Methods:  Patients with histologically confirmed indolent or aggressive lymphoma relapsed or refractory to ≥2 prior lines of treatment were eligible.  Patients received BAY 80-6946 at a dose of 0.8 mg/kg as a 1 hour infusion on days 1, 8 and 15 of a 28-day cycle.  Patients continued on therapy until disease progression or unacceptable toxicity. Responses were assessed every two cycles according to the response criteria for lymphoma (Cheson et al., JCO 17:1244,1999) or the guidelines for diagnosis and treatment of chronic lymphocytic leukemia (CLL; Hallek et al., Blood111:5446-56, 2008).   

Results:  As of July 31, 2013, a total of 61 lymphoma patients (27 indolent and 34 aggressive) were enrolled and 56 started study treatment.  Patients were similarly distributed among indolent and aggressive cohorts with respect to gender (52% female), median age (68 yr, range 22-90) and ethnicity (76% Caucasian) and were heavily pretreated (median number of prior therapies: 3; prior Rituximab: 84%; prior ASCT: 20%). Other characteristics included advanced stage III-IV in 85% and B symptoms in 17%. The following entities were represented: follicular (FL; n=13); CLL (n= 11); marginal zone (MZL; n=3; none staged to date); diffuse large B-cell (DLBCL; n=18); mantle cell (MCL; n=7); transformed (n=5); and peripheral T-cell (PTCL; n=4).  At the time of analysis patients had received between 1 and 5 cycles of treatment. Objective responses were seen across histologic subtypes (Table 1).  At the time of this interim analysis, the overall response rate (RR) and complete RR were 40% and 20% in FL, 67% and 0% in CLL, 83% and 17% in MCL, and 50% and 0% in PTCL, respectively.

Table 1. Best response by lymphoma subtype in staged patients

 

FL (n=10)

CLL (n=9)

DLBCL(n=17)

MCL(n=6)

Transformed(n=5)

PTCL(n=4)

CR/CRu

2

0

1

1

0

0

PR

2

6

1

4

1

2

SD

6

2

7

0

2

0

PD

0

1

8

1

2

2

CR – complete response; CRu – CR unconfirmed; PR – partial response; SD – stable disease; PD – progressive disease

Grade 3 adverse events (AE) were reported in 49% of patients, and grade 4 AE (all neutropenia) occurred in 15% of patients.  Grade 3/4 AEs occurring in ≥5% of patients included hypertension (31%), neutropenia (16%), hyperglycemia (13%), diarrhea (5%) and fatigue (5%). Hyperglycemia of any grade occurred in 47%.  Four patients required insulin therapy, but no grade 4 hyperglycemia was observed. Hypertension of any grade occurred in 46% of patients. Eight patients required antihypertensive treatment, but no grade 4 hypertension was reported. Diarrhea of any grade occurred in 25% of cases. No case of colitis was reported. There were two cases of interstitial pneumonitis, with both cases resolved following corticosteroid administration. Withdrawal of study drug due to AEs occurred in 10 patients (16%), and 4 patients required a dose reduction.  Four deaths occurred; 1 due to progressive disease, 1 due to acute respiratory insufficiency, 1 due to Cryptococcal meningitis and 1 due to sepsis after start of a salvage chemotherapy regimen.

Conclusions:  The novel PI3K inhibitor BAY 80-6946 is clinically active as a single agent and appears to have an acceptable toxicity profile in relapsed/refractory lymphoma. Preliminary efficacy results are encouraging, as promising activity has been observed in FL, CLL, MCL, and PTCL. The safety profile was consistent with prior studies. Further studies of this compound in patients with lymphoma are warranted.

Disclosures: Vitolo: Roche: Speakers Bureau ; Celgene: Speakers Bureau ; Takeda: Speakers Bureau . Mappa: Bayer S.p.A.: Employment . Giurescu: Bayer Pharma AG: Employment . Childs: Bayer HealthCare Pharmaceuticals: Employment .

*signifies non-member of ASH