Parsaclisib for R/R B-cell malignancies: Results of a phase I-II trial

On 25 February, Andres Forero-Torres from the University of Alabama at Birmingham, Alabama, USA, and colleagues, published in Blood the results of a phase I−II that investigated the safety of parsaclisib monotherapy and in combination with other treatments, in patients with relapsed or refractory (R/R) B-cell malignancies.

Parsaclisib is a next-generation, selective phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor and has shown promising activity in R/R B-cell malignancies either as single-agent or in combination in itacitinib, a Janus kinase 1 inhibitor. In this open-label, dose-escalation trial, CITADEL-101 (NCT02018861), the safety of parsaclisib  monotherapy or in combination with either itacitinib or rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) was assessed in R/R B-cell lymphomas. The primary endpoint of the trial was safety, tolerability and preliminary efficacy of parsaclisib monotherapy or in combination with R-ICE or itacitinib.   

Study design & baseline characteristics

• N = 72 patients with R/R B-cell malignancies, aged ≥ 18, who had received ≥ 1 prior line of treatment:
  • Chronic lymphocytic leukemia (CLL)
  • Diffuse large B-cell lymphoma (DLBCL)
  • Follicular lymphoma (FL)
  • Hodgkin lymphoma (HL)
  • Mantle cell lymphoma (MCL)
  • Marginal zone lymphoma (MZL)
  • Waldenstrom macroglobulinemia (WM)
  • Patients with Burkitt lymphoma and precursor B-lymphoblastic leukemia/lymphoma were excluded
• Six-part study design:
  • Part 1: Dose escalation of parsaclisib monotherapy
  • Part 2: Dose escalation of parsaclisib plus itacitinib
  • Part 3: Cohort expansions
  • Part 4-5: Were removed by a later protocol amendment (May 2016)
  • Part 6: Dose escalation and expansion of parsaclisib plus R-ICE
• Dosing:
  • Parsaclisib monotherapy: self-administration of a starting dose of 5 mg orally per day in a fasted state
  • Parsaclisib dose escalation (5−45 mg): 3 + 3 dose escalation design to identify dose-limiting toxicities (DLTs) within the 21-day observation period (Doses: 5 mg/ 10 mg/ 15 mg/ 20 mg/ 30 mg/ 45 mg):
    • If DLTs occurred in > 1 of the first three patients or a total of six patients, then the next lower tolerable dose was considered the maximum tolerated dose (MTD)
    • Due to long-term incidents of colitis, in November 2016 parsaclisib monotherapy was amended from daily administration the first nine weeks to weekly administration thereafter
  • Parsaclisib and itacitinib: 3 + 3 dose escalation design, starting with a parsaclisib dose approximately 25% less than the recommended dose determined for parsaclisib monotherapy. Itacitinib was co-administered at a dose of 300 mg once daily
  • Parsaclisib and R-ICE: 3 + 3 dose escalation design with a starting dose approximately 25% below the recommended dose determined for parsaclisib. R-ICE was administered in three 21-day cycles:
    • Rituximab: 375 mg/m² on Days 1 and 2 of cycle 1, and Day 1 of cycles 2 and 3
    • Ifosfamide: 5000 mg/m² by continuous intravenous (IV) infusion over 24 hours on Day 3 per cycle
    • Carboplatin: area under the curve 4 = 5 mg/mL; maximum dose 800 mg by IV infusion on Day 3
    • Etoposide: 100 mg/m² by IV on Days 3 to 5
  • Median patient age: 66 years
  • Patients with previous hematopoietic stem cell transplant: 29%
  • Patients with ≥ 3 prior treatment lines: 54%

Key results

Safety

• All parsaclisib single-agent doses up to 45 mg were well tolerated so no MTD was identified and the 20 mg and 30 mg (once daily) cohorts were expanded
• Pharmacokinetic analysis of multiple-dose administration of parsaclisib alone showed that parsaclisib reached peak plasma concentrations rapidly, with a median time to C_max of 0.5−1 hour. Parsaclisib plasma concentrations declined in a monophasic fashion with a mean terminal-phase disposition half-life of 8.6−5 hours
• In all cohorts, the most common any grade non-hematological treatment-emergent adverse events (TEAEs) were:
  • Diarrhea/colitis: 36%
  • Nausea: 36%
  • Fatigue: 31%
  • Rash: 31%
• Grade 3−4 neutropenia occurred in 19% of patients (n = 14)
• The most common serious AEs (SAEs) observed were:
  • Diarrhea/colitis: 13% (n = 9)
  • Pyrexia: 6% (n = 4)
  • Hypotension: 4% (n = 3)
  • Sepsis: 4% (n = 3)
• Any grade SAEs of infections and manifestations occurred in 15% of patients (n = 11)
• Median time to onset of Grade 3−4 diarrhea/colitis (range): 5.7 (1.6−9) months
• Median time to onset of Grade 3−4 rash (range): 2.9 (1.5−3) months
• Aspartate transaminase (AST) elevations occurred in 29% of patients (n = 21)
• Alanine transaminase (ALT) elevations occurred in 28% of patients (n = 20)
• Bilirubin elevation occurred in 11% of patients (n = 8)
• Parsaclisib dose interruption occurred in 42% of patients (n = 30):
  • Dose reduction: n = 4 patients (6%)
  • Treatment discontinuation: n =14 patients (9%)
• At data cut-off:
  • Patients who received once weekly parsaclisib (after receiving once daily for at least nine weeks): 35% of patients
  • Patients who once daily parsaclisib only: 64% of patients
• No Grade 4 hematological TEAEs were reported

Preliminary efficacy

• Efficacy rates for parsaclisib monotherapy:
• Overall response rate (ORR) by disease type:
  • DLBCL: 30% (n = 7/23)
  • FL: 71% (n = 10/14)
  • MZL: 78% (n = 7/9)
  • MCL: 67% (n = 6/9)
• Complete responses (CR) and complete metabolic responses (CMR) by disease type:
  • DLBCL: 17% (n = 4/23)
  • FL: 21% (n = 3/14)
  • MZL: 33% (n = 3/9)
  • MCL: 44% (n = 4/9)
• Partial responses (PR) and partial metabolic responses (PMR) by disease type:
  • DLBCL: 13% (n = 3/23)
  • FL: 50% (n = 7/14)
  • MZL: 44% (n = 4/9)
  • MCL: 22% (n = 2/9)
• Stable disease (SD) by disease type:
  • DLBCL: 17% (n = 4/23)
  • FL: 7% (n = 1/14)
  • MZL: 11% (n = 1/9)
  • MCL: 22% (n = 2/9)
• Progressive disease (PD) and progressive metabolic disease (PMD) by disease type:
  • DLBCL: 48% (n = 11/23)
  • FL: 14% (n = 2/14)
  • MZL: 11% (n = 1/9)
  • MCL: 0% (n = 0/9)
• Median duration of response by disease type:
  • DLBCL: 13.5 months (95% CI, 8.3−18.8)
  • FL: not reached
  • MZL 4.4 months (95% CI, 2.1−not evaluable)
  • MCL: not reached
• Among patients treated with parsaclisib plus itacitinib:
  • Best CR/CMR was achieved by CLL (n = 1/1) and FL (n = 1/1) patients
  • Best PMR was achieved by MCL (n = 1/1) and HL (n = 1/2) patients
• Among patients treated with parsaclisib plus R-ICE:
  • CMR was achieved by n = 3 patients
  • SD as best response: n = 2 patients

Conclusions

• Parsaclisib was not associated with clinically significant transaminitis
• The preliminary ORRs and good tolerability observed for parsaclisib monotherapy or in combination with other agents, indicates the need for further investigation into the potential benefit of this regimen for R/R B-cell malignancies