FDA places partial clinical hold on trials involving venetoclax in multiple myeloma 

On 19 March 2019, the U.S. Food and Drug Administration (FDA) placed a partial clinical hold on trials involving venetoclax (VENCLEXTA®/VENCYLXTO®) in the treatment of multiple myeloma (MM).

The decision is based on the results from the phase III BELLINI trial (NCT02755597) in relapsed/refractory MM (RRMM). In an FDA pre-planned analysis, there was a higher death rate (21% vs 11%) in the venetoclax arm compared to the placebo arm, of which 6.7% were determined to be treatment-emergent and over half were in the setting of progressive or refractory disease.

No new patients will be enrolled in studies using venetoclax until a further analysis is completed, though patients who are currently receiving venetoclax in clinical trials are permitted to continue treatment following a discussion with their treating physician. The FDA's decision is specific to the treatment of patients with MM and does not affect the use of venetoclax in other indications such as acute myeloid leukemia (AML).

Background

Venetoclax is a BCL-2 inhibitor currently approved by the FDA for the treatment of AML and chronic lymphocytic leukemia or small lymphocytic leukemia. It is currently being investigated in the MM setting in various combination treatments.

The BELLINI study design and results:

Results given as venetoclax versus placebo arm

• Multicenter, randomized, double-blind, phase III study (NCT02755597)
• Patients with RRMM
  • Prior lines of therapy: 1–3
  • Sensitive/naïve to proteasome inhibitors
• Regimen:
  • Bortezomib + dexamethasone _­+ venetoclax (venetoclax arm)
  • Bortezomib + dexamethasone + placebo (placebo arm)
• Primary endpoint of progression-free survival was met: 22.4 vs 15 months (HR 0.63, 95% CI, 0.44–0.90)
• Statistically significant improvements in:
  • Overall response rate: 82% vs 68%
  • Very good partial response or better: 59% vs 36%

The FDA review of BELLINI:

• Deaths: 21.1% (41/194) vs 11.3% (11/97)
• In the venetoclax arm:
  • Treatment-emergent deaths: 6.7% (n = 13) (HR 2.03, 95% CI, 1.042–3.945)
    • Of these, 8 were due to infection
    • Over 50% were in patients with refractory/progressive disease
  • Frequent causes of death not related to disease progression: sepsis, pneumonia, and cardiac arrest
• In the control arm:
  • Treatment-emergent deaths: 1% (n = 1)
• Severe, grade 3–5 toxicity: 86.5% vs 87.5%
• Serious adverse events (SAEs): 48.2% vs 50.0%
• Infections: 79.8% vs 77.1%
  • SAEs of infections: 28.0% vs 27.1%
  • Pneumonia: 20.7% vs 15.6%
    • SAEs of pneumonia: 14.0% vs 12.5%

Further analysis of the data is ongoing with the results expected to be published in a peer-reviewed journal and presented during a future medical congress.