Safety and efficacy of tenalisib in combination with romidepsin in patients with relapsed/refractory T-cell lymphoma: results from a phase I/II open-label multicenter study

by Selleckchem | Nov 11 2023

Tenalisib, a selective phosphoinositide-3-kinase δ/γ, and salt-inducible-kinase-3 inhibitor has shown efficacy and was well-tolerated in patients with T-cell lymphoma (TCL). In vitro studies suggest a synergistic anti-tumor potential for the combination of tenalisib with the histone-deacetylase inhibitor, romidepsin. This multicenter, open-label, phase I/II study was designed to characterize the safety, efficacy and pharmacokinetics of oral tenalisib twicedaily (BID) and intravenous (IV) romidepsin administered on Days 1, 8 and 15 in 28-day cycles in adults with relapsed/refractory TCL. Phase I/dose-escalation determined the MTD/optimal doses of tenalisib and romidepsin. The phase II/dose-expansion assessed the safety and anti-tumor activity of the combination at MTD/optimal dose. Overall, 33 patients were enrolled. In dose-escalation, no dose-limiting toxicity (DLT) was identified. Hence, the recommended doses for dose-expansion were tenalisib 800 mg BID orally, and romidepsin 14 mg/m2 IV. Overall treatment-emergent adverse events (TEAE) of any grade reported in >15% of patients were nausea, thrombocytopenia, increased aspartate aminotransferase, increased alanine aminotransferase, decreased appetite, neutropenia, vomiting, fatigue, anemia, dysgeusia, weight loss, diarrhea, and hypokalemia. Twenty-three patients (69.7%) had related ≥Grade 3 TEAE. The overall objective response rate in evaluable patients was 63.0% (PTCL: 75% and CTCL: 53.3%), with a complete response and partial response of 25.9% and 37.0% respectively. The median duration of response was 5.03 months. Coadministration of tenalisib and romidepsin did not significantly alter the pharmacokinetics of romidepsin. Overall, tenalisib and romidepsin combination demonstrated a favorable safety and efficacy profile supporting its further development for relapsed/refractory TCL.

Comments:

The study you've described involves the evaluation of a combination therapy using tenalisib, a selective phosphoinositide-3-kinase δ/γ and salt-inducible-kinase-3 inhibitor, along with romidepsin, a histone-deacetylase inhibitor, in patients with relapsed/refractory T-cell lymphoma (TCL). Here are the key findings and results from the study:

1. **Study Design**: This was a multicenter, open-label, phase I/II study aimed at assessing the safety, efficacy, and pharmacokinetics of the combination of oral tenalisib administered twice daily and intravenous romidepsin given on Days 1, 8, and 15 in 28-day cycles for adults with relapsed/refractory TCL.

2. **Phase I Dose-Escalation**: The initial phase of the study determined the Maximum Tolerated Dose (MTD) and optimal doses for tenalisib and romidepsin. Importantly, no dose-limiting toxicity (DLT) was identified during this phase.

3. **Recommended Doses**: Following the dose-escalation phase, the recommended doses for the subsequent dose-expansion phase were established as tenalisib 800 mg BID orally and romidepsin 14 mg/m2 IV.

4. **Safety and Tolerability**: The study reported treatment-emergent adverse events (TEAE) in >15% of patients. Common TEAEs included nausea, thrombocytopenia, liver enzyme elevations (increased aspartate aminotransferase and alanine aminotransferase), decreased appetite, neutropenia, vomiting, fatigue, anemia, dysgeusia, weight loss, diarrhea, and hypokalemia. A substantial portion of patients (69.7%) experienced TEAEs of grade 3 or higher.

5. **Efficacy**: The study evaluated the effectiveness of the combination therapy and reported an overall objective response rate of 63.0% in evaluable patients. This included complete responses in 25.9% of patients and partial responses in 37.0% of patients. Notably, the response rate varied between different types of TCL, with PTCL (Peripheral T-cell lymphoma) patients showing a higher response rate (75%) compared to CTCL (Cutaneous T-cell lymphoma) patients (53.3%).

6. **Duration of Response**: The median duration of response was reported as 5.03 months, indicating that the combination therapy had a notable impact on disease control.

7. **Pharmacokinetics**: The study also assessed the pharmacokinetics of romidepsin when coadministered with tenalisib and found that the combination did not significantly alter the pharmacokinetics of romidepsin.

8. **Conclusion**: The combination of tenalisib and romidepsin demonstrated a favorable safety and efficacy profile in patients with relapsed/refractory TCL. These findings support the further development of this combination therapy for TCL treatment.

It's important to note that this study provides promising results for the treatment of TCL, but additional research, including larger clinical trials, will be needed to confirm the efficacy and safety of this combination therapy and potentially lead to its approval for clinical use. Additionally, patient selection and individual considerations should be taken into account when deciding on treatment options for TCL.