Phase I/II study of a hybrid schedule of flavopiridol in relapsed/refractory mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL)

Abstract

8563 Background: Continuous infusion and bolus schedules of flavopiridol in MCL have yielded disappointing results. However, a pharmacologically derived hybrid schedule of administration is effective in refractory, genetically high-risk CLL, though life-threatening tumor lysis syndrome (TLS) may occur in patients with very high lymphocyte counts. Because flavopiridol decreases cyclin D1 and mcl-1 and induces apoptosis in MCL cells, is significantly toxic for cell lines derived from the activated B-cell-like type of DLBCL (OCI-Ly3) and down-regulates NF-kappa B, we investigated the hybrid schedule in MCL and DLBCL. Methods: Flavopiridol was administered as a 30-minute bolus (mg/m2) followed by a 4-hour continuous infusion (mg/m2), weekly for 4 doses every 6 weeks. Separate escalation rules applied to cycle 1 week 1 (C1W1) and all other weeks of treatment. Dose levels on C1W1 were DL1: 25/25 (4 pts); DL2: 30/30 (10 pts) and DL3: 30/50 (6 pts). Dose escalation on subsequent weeks was not possible due to toxicity and all pts received 30/50. All patients received TLS prophylaxis. Paired biopsy samples obtained before and after the first dose were analyzed for cdk targets. Results: Patient (n=20) characteristics: median age: 59 (r 24–80); male 15 (75%); median prior regimens 2 (r 1–6). 10 had MCL and 10 had DLBCL. Responses were PR in 2 (1 MCL; 1 DLBCL) pts (10%); SD in 5 (25%); and PD in 13 (65%). DLTs were TLS and severe vomiting/diarrhea in 2 pts at DL3. The MTD and phase II dose has not yet been defined. Other toxicities were grade 4 ANC (10 pts) requiring prophylactic G-CSF, TLS (1 pt) and bowel perforation (1 pt). Decreased Rb staining at the S807/811 phospho-site was noted in 8 of 9 paired samples analyzed (r 20–75%; p = 0.027) and at the S780 site in 7 of 8 paired samples (r 38–91%; p = 0.00016), suggestive of G1 cdk inhibition. In 1 sample in which p53 was detected, there was an increase post-treatment, suggestive of cdk9 inhibition. Conclusions: The hybrid schedule of flavopiridol has modest activity in relapsed MCL and DLBCL. TLS occurred infrequently and was reversible. DLTs were TLS and gastrointestinal toxicity. Accrual continues. Analysis of cell cycle and transcriptional cdk targets is ongoing. No significant financial relationships to disclose.