TREATMENT OF PRIMARY ADULT CHRONIC IMMUNE THROMBOCYTOPENIA (CITP) WITH FOSTAMATINIB, AN ORAL SYK INHIBITOR: RESULTS OF TWO RANDOMIZED, PLACEBO-CONTROLLED PHASE 3 STUDIES
(Abstract release date: 05/18/17)
EHA Library. Bussel J. 06/24/17; 181722; S435
Dr. James Bussel
Contributions
Contributions
Abstract
Abstract: S435
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 12:30 - 12:45
Location: Room N101
Background
ITP is characterized by autoantibody-directed platelet destruction mediated by activated monocyte Fc receptors which signal via spleen tyrosine kinase (syk). A Phase 2 trial of the oral syk inhibitor Fostamatinib (FOSTA) in 16 patients (pts) with refractory ITP provided preliminary efficacy and safety data (Podolanczuk et al., 2009).
Aims
To evaluate the efficacy and safety of FOSTA in adult cITP in 2 parallel, identical, multi-center, randomized, double-blind phase 3 studies (S047 and S048) of 24 weeks duration, followed by an open label study (S049).
Methods
150 pts with 3 platelet (plt) counts (ct) <30K/µL were enrolled (76 in S047, 74 in S048) with a 2:1 randomization to FOSTA 100 mg or placebo bid, and stratification by prior splenectomy and baseline plt ct < or ≥15K/μL. Sixty-one % of pts were female; median age was 54 y (20-88); 93% were Caucasian; 93% had cITP; median disease duration: 8.5 y; median baseline plt ct: 16K/μL. Prior therapies received by pts included 94% steroids, 47% TPO-RAs, 35% splenectomy, and 32% rituximab. Stable response (SR) was defined as a plt ct ≥50K/μL at 4 of 6 biweekly visits over Weeks 14-24; intermediate response (IR) as at least 2 consecutive bi-weekly plt cts ≥50K/μL, both without rescue treatment.
Results
Across both studies, a SR occurred in 18/101 (18%) FOSTA vs 1/49 (2%) placebo pts (p=0.007); 11 additional FOSTA and no placebo patients achieved an IR, making the overall response rate 29% (29/101) for FOSTA vs 2% (1/49) for placebo (p<0.0001). The median plt cts were 95K, 49K, 20.5K and 17.5K/μL in SR, IR, non-responders (NR) and placebo pts, respectively. In SR and IR, median time to first plt ct ≥50K/μL was 2 weeks. Age (< or ≥65 y), gender, baseline plt ct <15K/µL, prior TPO-RA or splenectomy did not substantially affect response. In S049, 9/41 (22%) pts newly treated with FOSTA have a SR, consistent with S047 and S048.
Fifty-four of 101 (54%) FOSTA pts and 14/49 (29%) placebo pts had a plt increase ≥20K/μL (p = 0.005). Three of 18 (17%) SR and 1/11 (9%) IR to FOSTA compared to 26/72 (36%) NR and 22/49 (45%) of the placebo group received ≥1 rescue medication, respectively. In S047-S048, serious bleeding occurred in 5.6% of the NR and 10.2% of placebo pts, but not in the 29 responders.
The number of pts with ≥ 1 adverse event (AE) was similar in FOSTA vs placebo (83% vs 75%). The majority AEs on FOSTA were mild or moderate; all resolved over time. Most common AEs were: diarrhea (29% vs 15%), nausea (19 vs 8%), hypertension (20% vs 8%), ALT/AST increase (10% vs 0%). Serious AEs were reported in 13% FOSTA vs 21% placebo pts.
Conclusion
Fostamatinib substantially improves plt cts in certain pts with heavily pre-treated, severe cITP of long disease duration. AEs are mostly mild or moderate in severity. Given its unique mechanism of action based on inhibition of syk, FOSTA could, if approved, be an important alternative as single agent and be a useful component of combination therapy for pts with difficult cITP.
Podolanczuk A et al. Of mice and men: an open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk. Blood. 2009;113:3154-60.
Session topic: 32. Platelets disorders
Keyword(s): Tyrosine kinase inhibitor, ITP, Autoimmune disease
Abstract: S435
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 12:30 - 12:45
Location: Room N101
Background
ITP is characterized by autoantibody-directed platelet destruction mediated by activated monocyte Fc receptors which signal via spleen tyrosine kinase (syk). A Phase 2 trial of the oral syk inhibitor Fostamatinib (FOSTA) in 16 patients (pts) with refractory ITP provided preliminary efficacy and safety data (Podolanczuk et al., 2009).
Aims
To evaluate the efficacy and safety of FOSTA in adult cITP in 2 parallel, identical, multi-center, randomized, double-blind phase 3 studies (S047 and S048) of 24 weeks duration, followed by an open label study (S049).
Methods
150 pts with 3 platelet (plt) counts (ct) <30K/µL were enrolled (76 in S047, 74 in S048) with a 2:1 randomization to FOSTA 100 mg or placebo bid, and stratification by prior splenectomy and baseline plt ct < or ≥15K/μL. Sixty-one % of pts were female; median age was 54 y (20-88); 93% were Caucasian; 93% had cITP; median disease duration: 8.5 y; median baseline plt ct: 16K/μL. Prior therapies received by pts included 94% steroids, 47% TPO-RAs, 35% splenectomy, and 32% rituximab. Stable response (SR) was defined as a plt ct ≥50K/μL at 4 of 6 biweekly visits over Weeks 14-24; intermediate response (IR) as at least 2 consecutive bi-weekly plt cts ≥50K/μL, both without rescue treatment.
Results
Across both studies, a SR occurred in 18/101 (18%) FOSTA vs 1/49 (2%) placebo pts (p=0.007); 11 additional FOSTA and no placebo patients achieved an IR, making the overall response rate 29% (29/101) for FOSTA vs 2% (1/49) for placebo (p<0.0001). The median plt cts were 95K, 49K, 20.5K and 17.5K/μL in SR, IR, non-responders (NR) and placebo pts, respectively. In SR and IR, median time to first plt ct ≥50K/μL was 2 weeks. Age (< or ≥65 y), gender, baseline plt ct <15K/µL, prior TPO-RA or splenectomy did not substantially affect response. In S049, 9/41 (22%) pts newly treated with FOSTA have a SR, consistent with S047 and S048.
Fifty-four of 101 (54%) FOSTA pts and 14/49 (29%) placebo pts had a plt increase ≥20K/μL (p = 0.005). Three of 18 (17%) SR and 1/11 (9%) IR to FOSTA compared to 26/72 (36%) NR and 22/49 (45%) of the placebo group received ≥1 rescue medication, respectively. In S047-S048, serious bleeding occurred in 5.6% of the NR and 10.2% of placebo pts, but not in the 29 responders.
The number of pts with ≥ 1 adverse event (AE) was similar in FOSTA vs placebo (83% vs 75%). The majority AEs on FOSTA were mild or moderate; all resolved over time. Most common AEs were: diarrhea (29% vs 15%), nausea (19 vs 8%), hypertension (20% vs 8%), ALT/AST increase (10% vs 0%). Serious AEs were reported in 13% FOSTA vs 21% placebo pts.
Conclusion
Fostamatinib substantially improves plt cts in certain pts with heavily pre-treated, severe cITP of long disease duration. AEs are mostly mild or moderate in severity. Given its unique mechanism of action based on inhibition of syk, FOSTA could, if approved, be an important alternative as single agent and be a useful component of combination therapy for pts with difficult cITP.
Podolanczuk A et al. Of mice and men: an open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk. Blood. 2009;113:3154-60.
Session topic: 32. Platelets disorders
Keyword(s): Tyrosine kinase inhibitor, ITP, Autoimmune disease
{{ help_message }}
{{filter}}