Velcade, Thalidomide, Dexamethasone and Panobinostat (VTD-P) for Patients with Relapsed and Relapsed/ Refractory Myeloma: Preliminary Results of the Muk-Six Phase I/IIa Trial
Authors: Popat Rakesh , Brown Sarah , Flanagan Louise M , Cavenagh James D. 
Published: October 2019

Introduction: Bortezomib (velcade), thalidomide and dexamethasone (VTD) is a standard of care regimen for patients with newly diagnosed and relapsed myeloma. The in vitro synergistic cytotoxicity between histone deacetylase and proteasome inhibitors has recently been confirmed by the PANORAMA 1 trial of panobinostat, bortezomib and dexamethasone. MUK-Six (ISRCTN: 59395590) is a multi-centre UK phase I/ IIa trial designed to determine the recommended dose (RD) of the pan-deacetylase inhibitor panobinostat in combination with VTD and to estimate the response rate at the RD within 16 cycles (primary endpoint). Here we report preliminary results of the dose escalation phase and ongoing patients treated at the RD.

Methods: Patients with relapsed and relapsed/ refractory myeloma that had between 1 and 4 prior lines of therapy received VTD-P (bortezomib 1.3mg/2sc days 1 and 8, thalidomide 100mg/ daily (50mg if pre-existing neuropathy), dexamethasone 20mg days 1, 2, 8, 9 and panobinostat days 1, 3, 5, 8, 10, 12) every 3 weeks. A rolling six dose escalation design was used to determine the maximum tolerated dose (MTD) and RD of panobinostat using protocol specified dose-limiting toxicity (DLT) criteria. The following panobinostat dose levels were used: cohort 1: 10mg; cohort 2: 15mg; cohort 3: 20mg. Those planned for autologous stem cell transplantation (ASCT) received a minimum of 6 cycles (maximal response plus 2 cycles) whereas those not suitable for ASCT could continue for up to 16 cycles of VTD-P followed by 1 year of panobinostat maintenance (days 1, 3, 5, 8, 10 and 12 of a 21 day cycle dosed at the RD). All patients treated with VTD-P received venous thrombosis prophylaxis as per institutional practice. Responses were assessed using modified IWG uniform response criteria and toxicity graded by CTCAE V4.0.

Results: Between January 2013 and July 2014 a total of 55 patients were registered, 19 to the dose escalation phase and 36 to the dose expansion phase. 7 were ineligible to start treatment and 9 were non-evaluable for efficacy analysis due to dose omissions during cycle 1. Patients were of a median of 62 years (41-76) and had received a median of 1 prior line of therapy (range 1-4). 29/48 (60.4%) had received prior bortezomib and 29/48 (60.4%) prior ASCT. Most patients were ISS I (26/48, 54.2%) with 10.4% (5/48) being ISS III. As of 28thJuly 2014, all patients in the dose escalation phase treated at the non-RD had completed treatment having received a median of 15 cycles (range 2-16). Only 1 DLT was observed during the dose escalation phase (cohort 3: hyponatremia ≥ grade 3) and as the criteria for MTD was not met, 20mg was declared to be the RD for dose expansion. Of the 9 patients treated at the non-RD, 8 (89%) achieved ≥ partial response.

33 patients treated at the RD were ongoing with treatment and have completed a median of 3 cycles (0-14). Of these, 24 are evaluable for response (out of a target 42 evaluable patients to be recruited). At this stage in an intent-to-treat analysis 15 of the 24 (62.5%, 80% confidence interval [47.4%-75.9%]) had achieved ≥ partial response, although 5 did not yet have response data available. The recruitment target of 42 patients at the RD is expected to be completed by the time of presentation and responses updated accordingly.

The VTD-P combination was generally well tolerated with no treatment discontinuations due to toxicity. Grade 3-4 toxicities included (number, %): hypophosphatemia (8, 16.7%), neutropenia (7, 14.6%), abnormal liver tests (3, 6.3%) (none observed at the non-RD); thrombocytopenia (3, 6.3%), peripheral neuropathy (1, 2.1%), diarrhoea (1, 2.1%) and hyperglycemia (1, 2.1%). The predominant grade 1-2 toxicities were: fatigue (31, 64.5%), neuropathy (28, 58.3%), constipation (22, 45.8%) and diarrhoea (17, 35.4%). 19 serious adverse events (SAEs) were reported by 12 patients at the RD, of which 4 were treatment related and predominantly gastrointestinal (GI).

Conclusions: This preliminary data demonstrates that VTD-P is a safe, well tolerated and potentially active regimen for patients with relapsed myeloma. The incidence of grade 3-4 GI and neurotoxicity was low and there were no discontinuations for toxicity. The RD of panobinostat was 20mg and enrolment to this expansion phase is currently ongoing. .

Acknowledgments: On behalf of the Myeloma UK Clinical Trial Network

Disclosures

Popat: Janssen: Honoraria. Off Label Use: Use of Panobinostat in relapsed myeloma. Cavenagh:Janssen: Honoraria; Celgene: Honoraria.