Venetoclax combination with R- or G-CHOP in NHL: Results from the phase Ib CAVALLI trial

On 8 March 2019, Andrew Zelenetz from Memorial Sloan Kettering Cancer Center, New York, USA, and colleagues, published in Blood results from the phase Ib trial CAVALLI, which compared venetoclax plus rituximab-based or obinutuzumab-based cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; R-CHOP versus G-CHOP) chemotherapy, in non-Hodgkin lymphoma (NHL) patients.

Preclinical results have indicated that venetoclax when combined with R or G exerts synergistic effects in vitro and in xenograft models in vivo. Thus, the aim of this multicenter, phase Ib CAVALLI trial (NCT02055820) was to assess the safety and determine a recommended dose for R-/G-CHOP chemotherapy for NHL in order to further investigate their activity in a future phase II trial. The primary endpoint was to determine the maximum tolerated dose (MTD) of venetoclax in combination with R- or G-CHOP in NHL patients. The main secondary endpoint was treatment efficacy.

Study design

• N = 56 patients aged ≥ 18 years with histologically-confirmed B-cell NHL, previously-untreated or with one previous therapy, excluding R-CHOP.
• Patient NHL subtypes (total cohort):
  • Follicular lymphoma (FL): n = 18
  • Diffuse large B-cell (DLBCL): n = 24
  • Other B-cell NHL: n = 14
• Most patients (91.1%) were not previously-treated with other regimens
• Mean patient age (range): 60.3 (37–79)
• Male patients: 62.5%
• Dosing:
  • Venetoclax (21-day cycles): Doses ranging from 200–800 mg once daily orally on Day 4 of cycle 1 and then on Day 1 for cycles 2–8
  • R-CHOP (Arm A; n 24):
    • R: 375 mg/m² intravenously (IV) on Day 1 for eight cycles
    • CHOP: (six or eight cycles): IV cyclophosphamide 750 mg/m², IV doxorubicin 50 mg/m², and IV vincristine b1.4 mg/m² (with a 2.0 mg cap) on Day 1, and prednisone 100 mg daily orally on Days 1–5
  • G-CHOP (Arm B; n = 32):
    • G: 1000 mg IV on Days 1, 8, and 15 of cycle 1 and on Day 1 of cycles 2–8
    • CHOP: (six or eight cycles): IV cyclophosphamide 750 mg/m², IV doxorubicin 50 mg/m², and IV vincristine b1.4 mg/m² (with a 2.0 mg cap) on Day 1, and prednisone 100 mg/day orally on Days 1–5
  • Mandatory tumor lysis syndrome (TLS) prophylaxis was orally administered by hydration and uric-acid reducing agent (i.e. allopurinol) in the first 72 hours prior to the first venetoclax dose
  • Granulocyte-colony stimulating factor (G-CSF) was administered in later protocol versions for all CHOP cycles
• Two-stage study:
  • Dose-escalation phase: venetoclax dose escalation. First dose in both arms was 200 mg/day for eight cycles
  • Dose and schedule selection: 3 + 3 design

Key results

• Dose-limiting toxicities were reported in 3 out of 14 patients at the first venetoclax dose (200 mg daily). For that dosing was changed from daily to 10 days per cycle and raised to 800 mg. A further reduction to 5 days per cycle occurred at the 800 mg dose level in the G-CHOP arm
• Median follow-up for patients achieving complete or partial response (CR/PR) at the end of treatment (range): 22 (11.4–36.4) months
• In the intention-to-treat (ITT) population:
  • Overall response rate (ORR) for both arms: 87.5%
  • CR rates:
    • R-CHOP + venetoclax: 79.2%
    • G-CHOP + venetoclax: 78.1%
  • ORR by histological subtype across both arms:
    • DLBCL: 88.9% (all CR)
    • FL: 83.3% (CR, 75%; PR, 8.3%)
    • Other histological subtypes: 71.4% (CR, 57.1%; PR, 14.3%)
  • Median PFS:
    • R-CHOP + venetoclax: not reached
    • G-CHOP + venetoclax: not reached
  • One-year PFS rates in DLBCL patients:
    • R-CHOP + venetoclax: 70%
    • G-CHOP + venetoclax: 100%
  • One-year PFS rates in FL patients:
    • R-CHOP + venetoclax: 100%
    • G-CHOP + venetoclax: 90%
  • Pharmacokinetic data from 49 patients showed that venetoclax exposures tested at 200, 400, 600, and 800 mg were similar when co-administered with R-CHOP or G-CHOP
  • Venetoclax plasma concentrations peaked at 4–8 hours and were comparable between the two arms

Safety

• Across both arms, the most common any grade adverse events (AEs) were:
  • Neutropenia: 57.1%
  • Nausea: 53.6%
• No deaths due to AEs occurred
• The most common Grade 3–4 AEs in the R-CHOP + venetoclax arm were:
  • Neutropenia: 54.2%
  • Febrile neutropenia: 33.3%
  • Thrombocytopenia: 16.7%
  • Anemia: 12.5%
• The most common Grade 3–4 AEs in the G-CHOP + venetoclax arm were:
  • Neutropenia: 59.4%
  • Febrile neutropenia: 25.0%
  • Thrombocytopenia: 37.5%
  • Anemia: 31.3%
• Median duration of treatment:
  • R-CHOP + venetoclax: 154 days
  • G-CHOP + venetoclax: 152 days
• A higher percentage of patients in the R-CHOP + venetoclax arm (71.9%) than in the G-CHOP + venetoclax arm (58.3%) experienced AEs leading to venetoclax dose reduction or discontinuation
• Patients discontinuing venetoclax treatment early: 30.3% (n = 16 patients in both arms):
  • Due to AEs: n = 16 patients
  • Due to progressive disease (PD): n = 1 patient
• Patients unable to complete ≥ 6 CHOP cycles due to AEs:
  • R-CHOP + venetoclax: 8.3% (n = 2/24)
  • G-CHOP + venetoclax: 18.8% (n = 6/32)

Conclusions

• Venetoclax plus R-CHOP or G-CHOP demonstrated manageable safety and promising activity in B-cell NHL patients
• Although the MTD was not reached, the recommended dose for venetoclax in combination with R-CHOP was 800 mg (Days 4-10, cycle 1; Days 1-10, cycles 2−8)
• R-CHOP plus venetoclax will be evaluated in first-line DLBCL patients in the phase II part of this study