A phase (Ph) I/II study of belinostat (Bel) in combination with cisplatin, doxorubicin, and cyclophosphamide (PAC) in the first-line treatment of advanced or recurrent thymic malignancies.
Anish Thomas, MD
Background: Belinostat is a hydroxamic acid histone deacetylase (HDAC) pan-inhibitor with single agent activity in thymic malignancies. PAC has activity against thymic cancers. Synergy between Bel and several chemotherapeutic agents, including P, A, and C, has been demonstrated in preclinical models.
Methods: Patients with histologically confirmed, treatment naive advanced thymic malignancies, PS<2, measurable disease, and adequate renal, hepatic and hematopoietic functions were eligible. Ph1 evaluated safety and tolerability of the combination using increasing dose levels (DL) of Bel (1000-2000 mg/m≤ over 48 h CIVI) and PAC (50/50/500 mg/m≤ IV/cycle) (3+3 dose escalation schema), administered every 21 days for no more than 6 cycles followed by optional maintenance Bel every 4 weeks. Primary end point of Ph2 is overall response rate (ORR). Results: From March 2010 to January 2012, 13 patients were enrolled [7 thymoma (T), 6 thymic carcinoma (TC); 8 in Ph1 and 5 in Ph2; median age: 49 years (range, 23-76)]. In Ph1, 6 patients were treated at DL1 (Bel 1000 mg/m2+ PAC) and 2 patients at DL2 (Bel 2000 mg/m2+ PAC). Dose Limiting Toxicities were Grade 3 nausea and diarrhea, and Grade 4 neutropenia and thrombocytopenia. Recommended phase II dose (RP2D) was set at DL1. Most common grade 3/4 treatment-related adverse events (AE) were lymphocytopenia (100%), leucopenia (85%), neutropenia (77%) thrombocytopenia (54%), anemia (38%), hypophosphatemia (38%), hypomagnesemia, hypokalemia, elevated AST, prolonged QTc and infusion-catheter related thromboembolic complications (23% each). Outcomes included one complete response (CR; T at DL1), 6 partial responses (PR; 4 T, 2 TC; 4 in Ph1, 2 in Ph2) and 6 stable disease (SD; 2 T, 4 TC; 3 each in Ph1 and Ph2). Four patients previously deemed unresectable underwent surgical resection.
Conclusions: Belinostat in combination with PAC has activity in thymic malignancies with a predicable AE profile. ORR was 54% including 33% PR in the TC subgroup. RP2D of the combination has been defined. Accrual to Ph2 part and molecular profiling of patient tumors is ongoing.
A phase II trial 90y-ibritumomab tiuxetan in combination with reduced intensity regimen of fludarabine (flu) and melphalan (mel) followed by allo-HCT in patients with refractory B-cell lymphoma.
Background: RIC allo-HCT has reduced transplant-related mortality (TRM) in patients with relapsed NHL. However, relapses do occur despite potential graft vs. lymphoma (GVL) effect. We hypothesized that adding Zevalin to Flu/Mel may improve disease control and reduce relapse post allo-HCT.
Methods: Patients received In- Zevalin on day -21 followed by 90Y- Zevalin 0.4mCi/kg on day -14, flu 25 mg/m2 daily on days -9 to -5 and mel 140 mg/m2 on day -4. Rituximab (R) level was measured on Day -22 and -15 and if the level was ≥ 10 μg/ml, R was not given prior to In-Zevalin or 90Y- Zevalin to enhance biodistribution. Tacrolimus and sirolimus was used for GVHD prophylaxis. Between 10/2007 and 11/2011, 31 were treated. Median age 55 (range 27-67), median regimen =3 (range 2-8). Median time from diagnosis to HCT was 20 mo (range 5-105). Histology: DLBCL (including transformed lymphoma)=14 (45%), MCL=7 (23%), FL=5 (16%) and SLL/CLL=5 (16%). Disease status at HCT: 1CR=7, Relapse=9, ≥2CR=5, primary refractory =10. Fifteen had chemoresistant and 19 had FDG PET+ at HCT. Donors: sib=13, URD=18.
Results: All patients engrafted with the median time to ANC ≥500 and platelet ≥ 20,000 was 14 (range 10-28) and 13.5 days (range 11-28), respectively. There were 10 deaths from disease progression (2) infection (5) GVHD (1) and multi-organ failure (2). TRM at day +100 and at 1 yr was 6.5% and 17%, Five with DLBCL relapsed between 3-7 mos. Grade II-IV acute GVHD was 65%, Grade III-IV was 16%, chronic GVHD was 65%. Fifteen became PET- at day +100 while 4 remained PET+ and relapsed. Twenty-one are alive at a median followup of 24 mos (range 2-46). The 2 yrs OS and PFS was 65% (95% CI, 51-75%) and 57% (95% CI, 46-67%), respectively. Univariate analysis identified disease status predict for OS and PFS while histology predict for PFS.
Conclusions: This study demonstrates the feasibility of adding Zevalin to flu/mel in the allo-HCT setting for B-cell NHL and suggest that this approach could be used to provide early disease control before GVL effect takes place. Innovative approaches should be explored in DLBCL.