Introduction
The Need for a Subcutaneous Formulation
Formulation of Subcutaneous Rituximab
Recombinant Human Hyaluronidase
Scientific Rationale
Pharmacokinetic Considerations
Pre-Clinical Studies
Clinical Studies
Study name | Study design | Patient population | Treatment regimen | Number of patients |
---|---|---|---|---|
SparkThera [45] (NCT00930514) | Phase Ib randomized, multicenter, two-stage dose-finding and dose-confirmation study | Previously untreated or treated FL | Stage 1 dose-finding: single cycle of R-SC test dose (375, 625, or 800 mg/m2) (control arm: R-IV 375 mg/m2), followed by R-IV maintenance (2 years) Stage 2 dose confirmation: R-SC 1400 mg q2 m for 12 cycles or q3 m for 8 cycles (control arm: ≤12 cycles R-IV 375 mg/m2) | Stage 1: 124 (108 R-SC, 16 R-IV) Stage 2: 154 (77 R-SC, 77 R-IV) |
Phase III randomized, multicenter, two-stage study | Previously untreated FL | Induction: 8 × q3w cycles of rituximab administered in combination with CHOP or CVP. Cycle 1 R-IV 375 mg/m2; Cycles 2–8 R-SC 1400 mg (control arm: cycles 2–8 R-IV 375 mg/m2) Maintenance: R-SC 1400 mg q8w for 2 years for patients with ≥PR to induction (control arm: R-IV 375 mg/m2) | Stage 1: 127 (63 R-SC, 64 R-IV) Stage 2: 283 Stage 1 + 2 total: 410 (205 R-SC, 205 R-IV) | |
Phase Ib, multicenter, two-part, dose-finding and dose confirmation study | Previously untreated CLL | Part 1 dose-finding: single cycle of R-SC test dose (1400, 1600, 1870 mg) with FC at cycle 6 Part 2 dose confirmation: 6 × q4w cycles of rituximab administered in combination with FC Cycle 1 R-IV 375 mg/m2; cycles 2–6 R-SC 1600 mg (control arm: cycles 2–6 R-IV 500 mg/m2) | Part 1: 64 (56 R-SC) Part 2: 176 (88 R-SC, 88 R-IV) | |
Phase IIIb randomized, open-label, multicenter study | Previously untreated DLBCL | 8 cycles of rituximab administered in combination with CHOP (6 or 8 cycles) q2w or q3w. Cycle 1 R-IV 375 mg/m2; Cycles 2–8 R-SC 1400 mg (control arm: Cycles 2–8 R-IV 375 mg/m2) | 576 (381 SC, 195 IV) | |
PrefMab [51] (NCT01724021) | Phase IIIb, open-label, randomized, multicenter, crossover study | Previously untreated DLBCL or FL | 8 cycles of rituximab administered in combination with CHOP, CVP, or bendamustinea. Arm A: Cycle 1 R-IV 375 mg/m2; Cycles 2–4 R-SC 1400 mg; Cycles 5–8 R-IV 375 mg/m2
Arm B: Cycles 1–4 R-IV 375 mg/m2; Cycles 5–8 R-SC 1400 mg | 743 (372 Arm A, 371 Arm B) |
MabCute [52] (NCT01461928) | Phase IIIb randomized, multicenter study | Relapsed/refractory iNHL | Induction: 8 cycles of rituximab q3w/q4w administered in combination with 6–8 cycles of CHOP or CVP. Cycle 1 R-IV 375 mg/m2; Cycles 2-8 R-SC 1400 mg. Maintenance I: R-SC 1400 mg q8w for 2 years in patients with ≥ PR following induction Maintenance IIc: R-SC 1400 mg q8w until disease progression (control arm: observation) | 216b
|
MabRella [54] (NCT01987505) | Phase IIIb, open-label, single-arm, safety umbrella study | Previously untreated DLBCL or FL | FL/DLBCL induction: q2w, q3w or q4w rituximab in combination with standard chemotherapy for 4– 7 cycles Cycle 1 R-IV 375 mg/m2; Cycles 2-8 R-SC 1400 mg FL maintenance: R-SC 1400 mg q2 m for 6–12 cycles | 336 |
Pharmacokinetic Studies: Dose Finding
Non-Hodgkin Lymphoma
Chronic Lymphocytic Leukemia
Pharmacokinetic Studies: Dose Confirmation
Non-Hodgkin Lymphoma
C
trough data | |||
---|---|---|---|
Study (rituximab dose) [dosing frequency/sampling time] | Rituximab C
trough (μg/ml) Geometric mean [95% CI] | Geometric mean ratio
C
trough(SC)/C
trough(IV) [90% CI] | |
SC | IV | ||
SparkThera (all SC doses; 375 mg/m2 IV) [q2 m/maintenance cycle 2] | 32.2a
[28.0–37.1] | 25.9a
[21.5–31.3] | 1.24 [1.02–1.51] |
SparkThera (all SC doses; 375 mg/m2 IV) [q3 m/maintenance cycle 2] | 12.1a
[10.1– 14.6] | 10.9a
[8.4– 14.1] | 1.12 [0.86–1.45] |
SABRINA (1400 mg SC; 375 mg/m2 IV) [q3w/induction cycle 7] | |||
Stage 1 | 134.6 [43.2%b] | 83.1 [36.7%b] | 1.62c
[1.36–1.94] |
Stage 2 | − | − | 1.5 [1.3–1.7] |
Pooled | 121 | 78 | 1.5 [1.4–1.7] |
SAWYER (1600 mg SC; 500 mg/m2 IV) [q4w/induction cycle 5] | 97.5 | 61.5 | 1.53 [1.27–1.85] |
AUC data | |||
---|---|---|---|
Study (rituximab dose) [dosing frequency/sampling time] | Rituximab AUC, μg·day/ml Geometric mean [95% CI] | Geometric mean ratio AUC(SC)/AUC(IV) [90% CI] | |
SC | IV | ||
SparkThera (all SC doses; 375 mg/m2 IV) [q2 m/maintenance cycle 2] | 5430a
[4980–5921] | 4012a
[3721–4326] | 1.35d
[1.23–1.49] |
SparkThera (all SC doses; 375 mg/m2 IV) [q3 m/maintenance cycle 2] | 5320a
[4880–5799] | 3947a
[3662–4255] | 1.35d
[1.23–1.48] |
SABRINA (1400 mg SC; 375 mg/m2 IV) [q3w/induction cycle 7] | 3779 | 2734 | 1.38c
[1.24–1.53] |
SAWYER (1600 mg SC; 500 mg/m2 IV) [q4w/induction cycle 6] | 4089 | 3630 | 1.10 [0.98–1.24] |
Chronic Lymphocytic Leukemia
Clinical Studies Confirming the Efficacy of Subcutaneous Rituximab
Non-Hodgkin Lymphoma
Study | Treatment group |
n
| Response rate (%) (95% CIa) | ||
---|---|---|---|---|---|
Completeb
| Partial | Overall | |||
SABRINAc
| R(SC) + chemo R(IV) + chemo | 205 | 32 (26–39) 32 (26–39) | 52 (45–59) 53 (46–60) | 84 (79–89) 85 (79–90) |
205 | |||||
MabEasec
| R(SC) + CHOP R (IV) + CHOP | 342 | 51 (45–56) 42 (35–50) | 32 (27–37) 36 (29–43) | 82 (78–86) 78 (71–84) |
177 | |||||
SAWYER Part 2d
| R(SC) + FC R(IV) + FC | 88 | 26 (17–37) 33 (23–44) | 59 (48–70) 48 (37–59) | 85 (76–92) 81 (71–88) |
88 |