Flavopiridol Can Be Safely Administered Using a Pharmacologically Derived Schedule and Demonstrates Activity In Relapsed and Refractory Non-Hodgkin's Lymphoma.
Authors: Jones Jeffrey A. , Andritsos Leslie , Baiocchi Robert , Benson Don M , Blum Kristie A. , Christian Beth , Deam Deidre , Flynn Joseph M. , Johnson Amy J. , Phelps Mitch A. , Porcu Pierluigi , Byrd John C. , Grever Michael R. 
Published: October 2019

Abstract 2834

Background:

A phase 2 study of flavopiridol administered according to a pharmacokinetically- (PK-) derived schedule has demonstrated significant activity in CLL, irrespective of high-risk genomic features. In combination with fludarabine and rituximab, flavopiridol has further shown promising activity in mantle cell lymphoma (MCL) and indolent B-cell non-Hodgkin's lymphoma (NHL). However, the safety and efficacy of single-agent flavopiridol administered on this schedule has not yet been characterized in patients with relapsed/refractory NHL.

Methods:

We conducted a standard cohorts-of-3 phase 1 trial to determine the maximum tolerated dose (MTD) and safety of single-agent flavopiridol in each of 4 groups: indolent B-NHL, aggressive B-NHL, MCL, and T-NHL. Adult patients (age >18y) with previously-treated (T-NHL '1 prior; B-NHL ≥2 prior), preserved end-organ function, adequate hematologic parameters (unless attributable to disease), and preserved performance status (≤ECOG 2) were eligible. Further, pts were only eligible if they had exhausted all other therapeutic options. All pts signed informed consent. Flavopiridol was given as a 30 min loading dose followed by a 4 hr infusion weekly for 4 weeks of a 6 week cycle (max 6 cycles). Dose levels (DL) 1, 2, and 3 were 30 mg/m2 + 30 mg/m2, 30 mg/m2 + 50 mg/m2, and 50 mg/m2 + 50 mg/m2, respectively. The first infusion was administered in hospital, but treatment could continue outpatient thereafter. Pts received allopurinol, phosphate binders, and Kayexalate (if pre-treatment K+ >4.5) prophylaxis for tumor lysis syndrome (TLS). Steroid pre-medication and/or treatment for cytokine release syndrome (CRS) was given at the discretion of the treating clinician. Dose-limiting toxicity (DLT) was generally defined as any grade 3/4 non-hematologic toxicity not resolving to ≤grade 2 within 2 wks or any grade 4 hematologic toxicity (except leukopenia/neutropenia) resulting in >1 wk treatment delay.

Results:

28 pts evaluable for toxicity have thus far completed cycle 1, which was used to define DLT: median age 66 years (range 34–84), 13 female (46%), median prior therapies 3 (range 1–8). All B-NHL patients received prior rituximab. Subsequent dose evaluation continues in the MCL and T-NHL arms. Across all pt groups, there were 11 pts at DL 1, 11 pts at DL 2, and 6 pts at DL 3. No DLTs have been observed to date. Median number of cycles received was 2. Seven pts completed all 6 cycles: 4 pts 30+30, 2 pts 30+50, 1 pt 50+50. Although no DLTs were observed, grade 3/4 hematologic toxicity was seen in 26 pts: neutropenia (23 pts), thrombocytopenia (3 pts), and anemia (7 pts). Grade 3 neutropenic fever and infection, however, were only observed in 2 and 5 pts, respectively. Common grade 3 non-hematologic toxicities included diarrhea (15 pts), fatigue (8 pts) and elevated transaminases (3 pts). Grade 3 CRS and TLS occurred in only 2 pts, both during cycle 1. Only 2 grade 4 non-hematologic toxicities (elevated transaminases, elevated lipase) were observed, both of which resolved without sequelae. Among pts completing ≥1 cycle, the most common reason for discontinuing treatment was disease progression (17 pts). One pt withdrew after diagnosis of a second cancer, 2 pts proceeded to transplant, and 2 pts withdrew for toxicity (1 persistent fatigue, 1 persistently elevated transaminases/malaise). Four pts expired on study: 3 progression, 1 sudden cardiac death unrelated to flavopiridol. Of 26 pts evaluable for response, 6 pts (21%) had partial responses: 2 follicular (30+30, 30+50), 1 SLL (50+50), 2 MCL (30+30, 30+50), and 1 DLBCL (50+50). Seven pts had stable disease for ≥1 cycle: 1 follicular (30+50), 1 MCL (30+30), 1 Richter's CLL (30+30), 1 DLBCL (50+50), and 3 PTCL (2 pts 30+30, 1 pt 30+50).

Conclusions:

Administered according to a PK-derived schedule, single-agent flavopiridol can be successfully delivered to multiply relapsed and/or refractory NHL pts with acceptable hematologic and non-hematologic toxicity. Both the promising activity and relative safety observed in these heavily pre-treated NHL pts warrant further investigation of this agent earlier in the course of disease and/or in combination with other agents, particularly in indolent B-cell and mantle cell NHL.

Disclosures:

Blum: Celgene : Research Funding.