Ublituximab and umbralisib for R/R B-cell NHL and CLL/SLL

Phosphoinositol-3-kinase (PI3K) inhibitors are a novel class of drugs being investigated for the treatment of patients with relapsed/refractory (R/R) B-cell malignancies. However, some, such as idelalisib, are associated with significant toxicity that requires careful management. Whilst newer agents have lower rates of toxicity, discontinuation due to adverse events (AEs) remains common. Umbralisib is a PI3K-δ inhibitor that is structurally distinct from other PI3K-δ inhibitors and has an improved target selectivity. Single agent studies have shown that umbralisib has a favorable safety profile, making it a viable candidate to be used in combination with other therapies.¹

Anti-CD20 monoclonal antibodies (mAbs), like rituximab, have become a core part of the treatment pathway of B-cell malignancies, like B-cell non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Ublituximab is a mAb targeting CD20, which is different from rituximab and other mAbs, since it has been glycoengineered to increase antibody-dependent cellular cytotoxicity (ADCC). In single agent studies, ublituximab has shown promising efficacy and a well-tolerated safety profile.¹

Preclinical studies indicate that umbralisib and ublituximab (U2) have synergistic activity, and so dual targeting of CD20 and PI3K may represent a new, efficacious treatment option for patients with B-cell malignancies. Therefore, Matthew Lunning, University of Nebraska Medical Center, Omaha, NE, US, and colleagues, conducted a phase I/Ib study (NCT02006485) to evaluate the safety and efficacy of U2, in patients with R/R B-cell NHL and CLL/SLL.¹

Study design and patient characteristics¹

• Phase I/Ib study at five sites in the US in patients with R/R B-cell NHL or CLL/SLL
  • Patients with NHL (n= 53) or CLL/SLL (n= 22) were accrued, analyzed and treated in separate cohorts
    • Phase I dose-escalation: patients with B-cell NHL or CLL/SLL who had relapsed after ≥1 prior therapy
    • Phase Ib dose expansion: patients with previously untreated CLL/SLL were eligible as well
  • Subtypes of B-cell NHL included: diffuse large B-cell lymphoma (DLBCL; n= 26), mantle cell lymphoma (MCL; n= 2), follicular lymphoma (FL; n= 19), marginal zone lymphoma (MZL; n= 5)) and Richter’s transformation (RT; n= 1)
  • Median age: 64 (26–86) years
  • Prior exposure to an anti-CD20 regimen: 96% (n= 72)
    • Refractory to prior anti-CD20 regimen: 54% (n= 39)
• Objectives:
  • Primary: determine maximum tolerated dose (MTD) and incidence of dose limiting toxicities (DLTs), as well as analyze the safety of U2
  • Secondary: determine overall response rate (ORR) and analyze duration of response (DOR)
• Phase I dose escalation: 3+3 design (n= 36)
  • Aim: determine MTD
  • Twelve cycles of fixed-dose intravenous (IV) ublituximab:
    • Patients with NHL: 900mg
    • Patients with CLL/SLL: 600mg or 900mg
    • Pre-medication with a corticosteroid and antihistamine
    • No dose reductions permitted
    • Patients in initial cohorts:
      • In cycle one and two: days one, eight and 15
      • In cycle four, six, nine and 12: day one
    • Study protocol amended mid-study:
      • In cycle one: days one, eight and 15
      • In cycles two to six: day one
      • In cycles three to seven: day one of every three cycles
• Oral umbralisib, once daily, at escalating doses, starting on day one of cycle one:
• Standard formulation: 800mg or 1200mg
• Micronized formulation: 400mg, 600mg, 800mg, 1000mg or 1200mg
• Phase Ib dose expansion (n= 39):
  • Aim: determine optimum recommended phase II dose (RP2D)
  • Oral umbralisib expansion cohorts:
    • Standard dose: 1200mg
    • Micronized dose: 800mg, 1000mg or 1200mg
    • Until disease progression (PD), toxicity or study removal
  • 900mg ublituximab IV
• After one year, patients could transfer to a compassionate-use extension study (NCT03207256)

Patient disposition¹

Discontinuations and dose reductions

• Final RP2Ds were determined to be:
  • Ublituximab: 900mg, IV, daily
  • Umbralisib: 800mg, orally, daily
• At data cut-off, 89% of patients have discontinued treatment:
  • Due to PD: 59%
  • Due to AEs: 13%
  • Achieved complete response (CR) and went on to transplant: 4%
  • Withdrew consent: 9%
  • Other reasons: 4%
• Eight patients remain on study (11%) at a median follow-up of 39 months
• Dose reductions with umbralisib: 15%
• Temporary hold of treatment:
  • Umbralisib: 39%
  • Ublituximab: 41%

Treatment duration

• Median treatment duration for the total cohort: 7.4 (0.3-7) months
  • Patients with CLL/SLL: 11 (2–40) months
  • Patients with indolent B-cell NHL (iNHL): 10 (1–44) months
  • Patients with aggressive B-cell NHL: 2 (0.3–52.7) months
  • Patients receiving the RP2D: 9.9 (0.6–52.7) months

MTD¹

• MTD: not reached in patients with CLL/SLL or B-cell NHL
• DLT; n= 1
  • Patient with CLL/SLL (600mg U2 and 800mg standard formula umbralisib)
    • Patient had baseline neutropenia (grade III) at entry that worsened to grade IV
    • Three additional patients were recruited at this dose
  • No DLTs in patients with B-cell NHL

Safety (n= 75)¹

• Median follow-up: 7.4 (0.3–52.7) months
• Most AEs were grade I-II
• Most common AEs of any grade: diarrhea, nausea, and fatigue (Table 1)
• One death occurred on-study, not deemed to be related to either study drug

Efficacy (n= 69)¹

• Analysis performed on all patients who had ≥ one post-treatment efficacy measurement (Table 2)
• Median follow-up: 8 (0.6-7) months
• ORR (CR + partial response [PR]) in total cohort: 46%
  • CR: 17%
• Median time to first response in total cohort: 8 (8–44) weeks
• Median DOR in total cohort: 20 months (95% CI, 11.3–not reached [NR])
  • Longest in patients with MZL
  • Shortest in patients with DLBCL
• Analysis in patients receiving ≥1200mg non-micronized umbralisib or >600mg micronized was also conducted (Table 3)

Conclusions¹

• The combination, U2, did not show cumulative toxicity distinct from the safety profile of either agent when used as monotherapy
• MTD was not reached in either cohort
• Final recommended doses for phase II:
  • Ublituximab: 900mg, IV, daily
  • Umbralisib: 800mg, orally, daily
• U2 combination had promising preliminary efficacy warranting further investigation
  • This was particularly prominent in patients with MZL (ORR: 100%)
• Limitations of study:
  • Lack of subtype assessment in patients with DLBCL
  • Lack of correlative studies to analyze mechanisms of resistance to dual antibody-PI3K therapy
  • Lack of assessment of prognostic factors
  • Limited sample sizes for histological analysis
  • Absence of pharmacokinetic data for U2

Future directions

This study has informed other ongoing studies of the preliminary activity of U2:

• UNITY-CLL (NCT02612311); phase III study, U2 versus obinutuzumab + chlorambucil versus ublituximab or umbralisib alone in patients with CLL²
• UNITY-NHL (NCT02793583); phase II/III randomized study comparing U2 with or without bendamustine or umbralisib alone in patients with B-cell NHL³
• Phase I/II study of U2 + pembrolizumab in CLL and RT (NCT02535286)⁴
• Phase I study comparing U2 to U2 with or without ibrutinib or bendamustine in patients with B-cell NHL or CLL/SLL (NCT02006485)⁵