EHA Library - The official digital education library of European Hematology Association (EHA)

PHASE 1 FINAL RESULTS AND PHASE 2A DOSE SELECTION FOR CERDULATINIB (PRT062070) A DUAL SYK/JAK INHIBITOR IN PATIENTS WITH RELAPSED/REFRACTORY B CELL MALIGNANCIES –
Author(s): ,
Paul Hamlin
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Ian Flinn
Affiliations:
Sarah Cannon Research Institute,Nashville,United States
,
Nina Wagner-Johnston
Affiliations:
Johns Hopkins University,Baltimore,United States
,
Jan Burger
Affiliations:
MD Anderson Cancer Center,Houston,United States
Glenn Michelson
,
Glenn Michelson
Affiliations:
,
Anjali Pandey
Affiliations:
Portola Pharmaceuticals Inc,South San Francisco,United States
,
Matt Birrell
Affiliations:
Portola Pharmaceuticals Inc,South San Francisco,United States
,
Greg Coffey
Affiliations:
Portola Pharmaceuticals Inc,South San Francisco,United States
,
Janet Leeds
Affiliations:
Portola Pharmaceuticals Inc,South San Francisco,United States
,
Alice Sabalvaro-Torres
Affiliations:
Portola Pharmaceuticals Inc,South San Francisco,United States
,
Yvonne Kim
Affiliations:
Portola Pharmaceuticals Inc,South San Francisco,United States
,
John Curnutte
Affiliations:
Portola Pharmaceuticals Inc,South San Francisco,United States
Manish Patel
Affiliations:
Florida Cancer Specialists,Sarasota,United States
(Abstract release date: 05/19/16) EHA Library. Hamlin P. 06/09/16; 135363; LB2252
Dr. Paul Hamlin
Dr. Paul Hamlin
Contributions
Abstract
Abstract: LB2252

Type: Eposter Presentation

Background
Subsets of B cell lymphomas demonstrate a reliance on B-cell antigen receptor (BCR) and/or cytokine JAK/STAT signaling for survival.  SYK is upstream of BTK, PI3Kδ, and PLCγ2 on the BCR pathway, making it a potential therapeutic target.  Additional survival mechanisms are mediated by cytokine-induced JAK/STAT pathways, derived from the tumor or tumor infiltrating leukocytes, which leads to upregulation of BCL2 family members.  In pre-clinical tumor models, cerdulatinib induces apoptosis in a genetically diverse panel of cell lines and primary B cell tumors in the 1 to 2 µM range.

Aims
The primary aim of the study was to establish the maximum tolerated dose of cerdulatinib.

Methods
This is a 3+3 dose escalation study with 28-day cycles.  Once daily (QD; up to 100 mg) and twice daily (BID; up to 45 mg) dosing was evaluated.  Pharmacokinetics (PK), pharmacodynamics (PD), and safety were monitored, as well as an initial assessment of efficacy.  Clinical response was assessed by standard criteria.  Potency and specificity for SYK and JAK pathway inhibition were measured in whole blood assays by monitoring signaling responses following ligation of the BCR and receptors for IL2, IL4, IL6, and GM-CSF. Serum markers of inflammation were also measured.

Results
43 patients with CLL/SLL or B-cell NHL were enrolled on the completed phase 1.  Median age is 67 years (range 23-85) and median prior therapies is 3 (range 1-8).  Treatment related AEs ≥ grade 3 occurring in 2 or more patients with daily dosing were: fatigue (n=5), anemia and neutropenia (n=3 each), and abdominal pain, neutrophil count decrease, and pneumonia (n=2 each).  A number of these events occurred in the setting of progressive disease.  The highest overall exposure was achieved at the 45 mg BID dose, in which 2 DLTs occurred: grade 3 pancreatitis and grade 3 fatigue.  Enrollment to this dose was discontinued, and the phase 2a dose was selected.  In review of the 40-100 mg QD doses, the average SS Cmin and Cmax concentrations plateaued at 0.70 ± 0.20 and 1.38 ± 0.23 µM, respectively.  QD dosing of 40-100 mg resulted in 50 to 100% (SS Cmin to Cmax) inhibition of SYK and JAK signaling in peripheral blood, and significant inhibition of serum markers of inflammation.   The extent of inhibition of SYK and JAK signaling as well as inhibition of serum markers of inflammation significantly correlated with tumor response.  While the PK is suitable for QD dosing with a t1/2 of 12-16 hours and a 2:1 peak-trough ratio, the pH dependent low solubility of cerdulatinib limited dissolution, and physiologic modeling suggested that BID dosing would increase overall exposure.  This was accomplished with the 45 mg BID dose, where complete inhibition of SYK and JAK at SS Cmin (~1.5 µM) in peripheral blood assays was observed, consistent with an approximate doubling in exposure.    Partial responses in phase 1 were observed in 5 heavily pretreated patients with CLL, FL, and transformed DLBCL at doses ranging from 30-65 mg QD. Two PRs were observed in the 45 mg BID dose group, one in a patient with FL and another with CLL.  Responses typically occurred after 2 cycles of treatment.  Multiple patients have demonstrated nodal reductions and maintained clinical benefit for over a year.  Based on the PK/AE profile, there appeared to be higher grades of adverse events at SS Cmin of 1.25 µM or greater.  PK modeling indicated a dose of 35 mg BID would yield a SS Cmin of 1.02 µM and a SS Cave of 1.16 µM, which is predicted to be tolerable, efficacious, and achieve complete inhibition of SYK and JAK in peripheral blood.  35 mg BID was therefore selected as the phase 2a dose.

Conclusion
Cerdulatinib demonstrates clinical activity in heavily pretreated patients with CLL/B-cell NHL and is generally well tolerated.  BID dosing has overcome the previous plateau in exposure and has enhanced PD effects.  A phase 2a study is now open for CLL/SLL, FL/other indolent NHL and aggressive B-cell NHL at a dose of 35 mg BID.

Session topic: E-poster

Keyword(s): Chronic lymphocytic leukemia, Non-Hodgkin's lymphoma, Tyrosine kinase inhibitor
Abstract: LB2252

Type: Eposter Presentation

Background
Subsets of B cell lymphomas demonstrate a reliance on B-cell antigen receptor (BCR) and/or cytokine JAK/STAT signaling for survival.  SYK is upstream of BTK, PI3Kδ, and PLCγ2 on the BCR pathway, making it a potential therapeutic target.  Additional survival mechanisms are mediated by cytokine-induced JAK/STAT pathways, derived from the tumor or tumor infiltrating leukocytes, which leads to upregulation of BCL2 family members.  In pre-clinical tumor models, cerdulatinib induces apoptosis in a genetically diverse panel of cell lines and primary B cell tumors in the 1 to 2 µM range.

Aims
The primary aim of the study was to establish the maximum tolerated dose of cerdulatinib.

Methods
This is a 3+3 dose escalation study with 28-day cycles.  Once daily (QD; up to 100 mg) and twice daily (BID; up to 45 mg) dosing was evaluated.  Pharmacokinetics (PK), pharmacodynamics (PD), and safety were monitored, as well as an initial assessment of efficacy.  Clinical response was assessed by standard criteria.  Potency and specificity for SYK and JAK pathway inhibition were measured in whole blood assays by monitoring signaling responses following ligation of the BCR and receptors for IL2, IL4, IL6, and GM-CSF. Serum markers of inflammation were also measured.

Results
43 patients with CLL/SLL or B-cell NHL were enrolled on the completed phase 1.  Median age is 67 years (range 23-85) and median prior therapies is 3 (range 1-8).  Treatment related AEs ≥ grade 3 occurring in 2 or more patients with daily dosing were: fatigue (n=5), anemia and neutropenia (n=3 each), and abdominal pain, neutrophil count decrease, and pneumonia (n=2 each).  A number of these events occurred in the setting of progressive disease.  The highest overall exposure was achieved at the 45 mg BID dose, in which 2 DLTs occurred: grade 3 pancreatitis and grade 3 fatigue.  Enrollment to this dose was discontinued, and the phase 2a dose was selected.  In review of the 40-100 mg QD doses, the average SS Cmin and Cmax concentrations plateaued at 0.70 ± 0.20 and 1.38 ± 0.23 µM, respectively.  QD dosing of 40-100 mg resulted in 50 to 100% (SS Cmin to Cmax) inhibition of SYK and JAK signaling in peripheral blood, and significant inhibition of serum markers of inflammation.   The extent of inhibition of SYK and JAK signaling as well as inhibition of serum markers of inflammation significantly correlated with tumor response.  While the PK is suitable for QD dosing with a t1/2 of 12-16 hours and a 2:1 peak-trough ratio, the pH dependent low solubility of cerdulatinib limited dissolution, and physiologic modeling suggested that BID dosing would increase overall exposure.  This was accomplished with the 45 mg BID dose, where complete inhibition of SYK and JAK at SS Cmin (~1.5 µM) in peripheral blood assays was observed, consistent with an approximate doubling in exposure.    Partial responses in phase 1 were observed in 5 heavily pretreated patients with CLL, FL, and transformed DLBCL at doses ranging from 30-65 mg QD. Two PRs were observed in the 45 mg BID dose group, one in a patient with FL and another with CLL.  Responses typically occurred after 2 cycles of treatment.  Multiple patients have demonstrated nodal reductions and maintained clinical benefit for over a year.  Based on the PK/AE profile, there appeared to be higher grades of adverse events at SS Cmin of 1.25 µM or greater.  PK modeling indicated a dose of 35 mg BID would yield a SS Cmin of 1.02 µM and a SS Cave of 1.16 µM, which is predicted to be tolerable, efficacious, and achieve complete inhibition of SYK and JAK in peripheral blood.  35 mg BID was therefore selected as the phase 2a dose.

Conclusion
Cerdulatinib demonstrates clinical activity in heavily pretreated patients with CLL/B-cell NHL and is generally well tolerated.  BID dosing has overcome the previous plateau in exposure and has enhanced PD effects.  A phase 2a study is now open for CLL/SLL, FL/other indolent NHL and aggressive B-cell NHL at a dose of 35 mg BID.

Session topic: E-poster

Keyword(s): Chronic lymphocytic leukemia, Non-Hodgkin's lymphoma, Tyrosine kinase inhibitor

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies