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THE DUAL SYK/JAK INHIBITOR CERDULATINIB DEMONSTRATES COMPLETE INHIBITION OF SYK AND JAK AND RAPID TUMOR RESPONSES IN A PHASE 2 STUDY IN PATIENTS WITH RELAPSED/REFRACTORY B CELL MALIGNANCIES
Author(s):
Paul Hamlin
,
Paul Hamlin
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
Charles Farber
,
Charles Farber
Affiliations:
Carol G. Simon Cancer Center,Morristown, NJ,United States
Timothy Fenske
,
Timothy Fenske
Affiliations:
Division of Hematology & Oncology,Medical College of Wisconsin,Milwaukee, WI,United States
James Khatcheressian
,
James Khatcheressian
Affiliations:
Virginia Cancer Institute,Richmond, VA,United States
Carole Miller
,
Carole Miller
Affiliations:
St. Agnes Hospital Cancer Center,Baltimore, MD,United States
Javier Munoz
,
Javier Munoz
Affiliations:
Banner MD Anderson Cancer Center,Gilbert, AZ,United States
Manish Patel
,
Manish Patel
Affiliations:
Florida Cancer Specialists/Sarah Cannon Research Center,Sarasota, FL,United States
Sonali Smith
,
Sonali Smith
Affiliations:
University of Chicago,Chicago, IL,United States
Don Stevens
,
Don Stevens
Affiliations:
Norton Cancer Institute,Louisville, KY,United States
Anjali Pandey
,
Anjali Pandey
Affiliations:
Portola Pharmaceuticals,South San Francisco,United States
Matt Birrell
,
Matt Birrell
Affiliations:
Portola Pharmaceuticals,South San Francisco,United States
Janet Leeds
,
Janet Leeds
Affiliations:
Portola Pharmaceuticals,South San Francisco,United States
Y. Lynn Wang
,
Y. Lynn Wang
Affiliations:
Department of Pathology,University of Chicago,Chicago, IL,United States
Greg Coffey
,
Greg Coffey
Affiliations:
Portola Pharmaceuticals,South San Francisco,United States
John Curnutte
John Curnutte
Affiliations:
Portola Pharmaceuticals,South San Francisco,United States
(Abstract release date: 05/18/17) EHA Library. Hamlin P. 06/25/17; 182060; S773
Dr. Paul Hamlin
Dr. Paul Hamlin
Contributions
PDF Abstract
Abstract

Abstract: S773

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 09:00 - 09:15

Location: Hall A

Background

Subsets of B cell malignancies are addicted to B cell antigen receptor (BCR) signaling for survival.  Co-stimulation of the BCR with IL-2 or IL-4 in normal B cells significantly enhances cellular activation relative to BCR or cytokine stimulation alone, and combining SYK selective and JAK selective inhibitors synergize to suppress this response (Coffey et al., 2013).  Hence, BCR/SYK and cytokine JAK/STAT signals cooperate to control B cell activation.  This cooperation appears to be relevant to B cell malignancies as well.  IL-4 promotes the survival of CLL cells in culture via up-regulation of MCL1 and BCLXL, protecting the tumor from death induced by fludarabine and chlorambucil (Steele et al., 2010) and by idelalisib and ibrutinib (Aguilar-Hernandez et al., 2016).  Also, unlike ibrutinib, combined SYK and JAK inhibition by cerdulatinib induces apoptosis in primary CLL cells and leads to down-regulation of MCL1 and BCLXL (Blunt et al., 2015) and induces apoptosis in cells from ibrutinib-resistant CLL patients (Guo et al., 2017). It also induces apoptosis in primary DLBCL and DLBCL cell lines that carry BCR pathway mutations resistant to ibrutinib (Ma et al, 2015). Combined SYK/JAK inhibition may therefore represent a powerful strategy to control B cell malignancies. 
A phase I dose escalation study of cerdulatinib in 43 patients with relapsed/refractory CLL and NHL was recently completed (Hamlin et al., EHA Congress 2016).  Inhibition of both BCR/SYK and JAK/STAT signaling pathways by >90% in peripheral blood assays was well tolerated.  Durable PRs and 1 CR were observed in CLL and FL, including in patients who had relapsed on prior BCR inhibitor therapy.  No consistent hepatic toxicity, anemia, thrombocytopenia or neutropenia was observed.  Two grade 3 dose limiting toxicities were observed at 45 mg BID (fatigue, pancreatitis).  35 mg BID was identified as the Phase 2 dose based on Phase 1 data and on PK/PD modeling. 

Aims
The primary aim of the study was to understand the safety and activity of cerdulatinib in B-cell malignancies.

Methods
This is an open-label study with 28-day cycles.  Twice daily (BID; 30 mg and 35 mg) dosing was evaluated.  Pharmacokinetics (PK), pharmacodynamics (PD), and safety were monitored, as well as an 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 IL-4. Serum markers of inflammation, minimal residual disease (MRD) and apoptosis in CLL patients were also measured.

Results
A phase 2 study was initiated in May 2016 to enroll up to 40 patients in each of three cohorts; 1) relapsed/refractory CLL/SLL, 2) relapsed/refractory indolent NHL, and 3) relapsed DLBCL, MCL and transformed FL.  As of March 1, 2017, 37 patients have been enrolled, 17 with CLL/SLL, 15 with indolent NHL (10 FL, 4 MZL, 1 WM), and 5 with aggressive NHL (3 DLBCL, 1 MCL, 1 tFL).  Median patient age is 70 years (range, 51-93).  The median number of prior therapies is 3 (range 1–7).  11 patients had prior BTK or PI3K inhibitor therapy.

The safety profile has been similar to what was seen in the Phase 1 study.  However, 3 patients at 35 mg BID achieved higher than expected drug concentrations and had SAEs (2 grade 5 infections, 1 grade 3 pancreatitis).  The starting dose was reduced to 30 mg BID and a PK monitoring and dose reduction strategy has been implemented.  To date, this has resulted in a better safety profile without PK outliers.  The most common AEs of any grade have been diarrhea (27%), fatigue (27%) and nausea (24%).  Grade 3+ AEs occurring in more than 1 patient are infection (5 patients), abdominal pain (3 patients) and hypertension (3 patients). 
As seen in phase 1, significant inhibition of SYK and JAK signaling pathways in peripheral blood is observed.  Evidence for tumor cell mobilization to peripheral blood in CLL/SLL is consistently observed following one week of therapy.  PRs have been seen in all 3 cohorts including 10 of 13 (77%) CLL/SLL and 3 of 6 (50%) FL patients evaluated.  Of these 13 PRs, 12 are still on drug with 4 patients in response for greater than 6 months.  In addition, PRs have been seen in patients who relapsed on ibrutinib (FL patient, 8+ months) and venetoclax (SLL patient, 7+ months) therapy. As demonstrated preclinically, we have seen evidence of apoptosis (Annexin V+ B-cells) in 6 CLL patients.  5 of these patients had a PR at the end of the 2nd cycle.  

Conclusion
Cerdulatinib demonstrates clinical activity in heavily pretreated patients with CLL/B-cell NHL and is generally well tolerated.  Consistent activity is seen in patients with CLL and FL.  Accrual is proceeding; updated PK/PD, safety and efficacy will be presented.

Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical

Abstract: S773

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 09:00 - 09:15

Location: Hall A

Background

Subsets of B cell malignancies are addicted to B cell antigen receptor (BCR) signaling for survival.  Co-stimulation of the BCR with IL-2 or IL-4 in normal B cells significantly enhances cellular activation relative to BCR or cytokine stimulation alone, and combining SYK selective and JAK selective inhibitors synergize to suppress this response (Coffey et al., 2013).  Hence, BCR/SYK and cytokine JAK/STAT signals cooperate to control B cell activation.  This cooperation appears to be relevant to B cell malignancies as well.  IL-4 promotes the survival of CLL cells in culture via up-regulation of MCL1 and BCLXL, protecting the tumor from death induced by fludarabine and chlorambucil (Steele et al., 2010) and by idelalisib and ibrutinib (Aguilar-Hernandez et al., 2016).  Also, unlike ibrutinib, combined SYK and JAK inhibition by cerdulatinib induces apoptosis in primary CLL cells and leads to down-regulation of MCL1 and BCLXL (Blunt et al., 2015) and induces apoptosis in cells from ibrutinib-resistant CLL patients (Guo et al., 2017). It also induces apoptosis in primary DLBCL and DLBCL cell lines that carry BCR pathway mutations resistant to ibrutinib (Ma et al, 2015). Combined SYK/JAK inhibition may therefore represent a powerful strategy to control B cell malignancies. 
A phase I dose escalation study of cerdulatinib in 43 patients with relapsed/refractory CLL and NHL was recently completed (Hamlin et al., EHA Congress 2016).  Inhibition of both BCR/SYK and JAK/STAT signaling pathways by >90% in peripheral blood assays was well tolerated.  Durable PRs and 1 CR were observed in CLL and FL, including in patients who had relapsed on prior BCR inhibitor therapy.  No consistent hepatic toxicity, anemia, thrombocytopenia or neutropenia was observed.  Two grade 3 dose limiting toxicities were observed at 45 mg BID (fatigue, pancreatitis).  35 mg BID was identified as the Phase 2 dose based on Phase 1 data and on PK/PD modeling. 

Aims
The primary aim of the study was to understand the safety and activity of cerdulatinib in B-cell malignancies.

Methods
This is an open-label study with 28-day cycles.  Twice daily (BID; 30 mg and 35 mg) dosing was evaluated.  Pharmacokinetics (PK), pharmacodynamics (PD), and safety were monitored, as well as an 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 IL-4. Serum markers of inflammation, minimal residual disease (MRD) and apoptosis in CLL patients were also measured.

Results
A phase 2 study was initiated in May 2016 to enroll up to 40 patients in each of three cohorts; 1) relapsed/refractory CLL/SLL, 2) relapsed/refractory indolent NHL, and 3) relapsed DLBCL, MCL and transformed FL.  As of March 1, 2017, 37 patients have been enrolled, 17 with CLL/SLL, 15 with indolent NHL (10 FL, 4 MZL, 1 WM), and 5 with aggressive NHL (3 DLBCL, 1 MCL, 1 tFL).  Median patient age is 70 years (range, 51-93).  The median number of prior therapies is 3 (range 1–7).  11 patients had prior BTK or PI3K inhibitor therapy.

The safety profile has been similar to what was seen in the Phase 1 study.  However, 3 patients at 35 mg BID achieved higher than expected drug concentrations and had SAEs (2 grade 5 infections, 1 grade 3 pancreatitis).  The starting dose was reduced to 30 mg BID and a PK monitoring and dose reduction strategy has been implemented.  To date, this has resulted in a better safety profile without PK outliers.  The most common AEs of any grade have been diarrhea (27%), fatigue (27%) and nausea (24%).  Grade 3+ AEs occurring in more than 1 patient are infection (5 patients), abdominal pain (3 patients) and hypertension (3 patients). 
As seen in phase 1, significant inhibition of SYK and JAK signaling pathways in peripheral blood is observed.  Evidence for tumor cell mobilization to peripheral blood in CLL/SLL is consistently observed following one week of therapy.  PRs have been seen in all 3 cohorts including 10 of 13 (77%) CLL/SLL and 3 of 6 (50%) FL patients evaluated.  Of these 13 PRs, 12 are still on drug with 4 patients in response for greater than 6 months.  In addition, PRs have been seen in patients who relapsed on ibrutinib (FL patient, 8+ months) and venetoclax (SLL patient, 7+ months) therapy. As demonstrated preclinically, we have seen evidence of apoptosis (Annexin V+ B-cells) in 6 CLL patients.  5 of these patients had a PR at the end of the 2nd cycle.  

Conclusion
Cerdulatinib demonstrates clinical activity in heavily pretreated patients with CLL/B-cell NHL and is generally well tolerated.  Consistent activity is seen in patients with CLL and FL.  Accrual is proceeding; updated PK/PD, safety and efficacy will be presented.

Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical

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