Abstract
Background: The histone deacetylase inhibitor (HDACi) romidepsin, while a clear advance for relapsed peripheral and cutaneous T cell lymphomas (CTCL and PTCL), induces short durations of remission at 9 to 10 months (Piekarz et al., 2011 and Coiffier et al., 2011). Other HDACi have been evaluated in other lymphoma types including Hodgkin lymphoma (HL) with panobinostat having a 27% ORR in patients with post-ASCT relapsed disease (Younes et al., 2012).
The aurora A kinase inhibitor alisertib has shown promising results to date including in a phase II sponsored trial (Friedberg et al., 2011) in which the ORR was 32% with responses of 100% in Burkitt lymphoma (BL), 20% in diffuse large B cell lymphoma (DLBCL), and 57% in PTCL. Recent data from a SWOG further showed an ORR of 20% in all TCL and 50% in PTCL (Barr et al., 2014), and a registration trial is ongoing in relapsed PTCL.
Preclinical data supports the combination of an aurora A kinase inhibitor plus a HDACi. The pan-aurora kinsase inhibitor MK-0457 in combination with the HDACi vorinostat enhanced lymphoma cell death through repression of C-Myc and C-Myc responsive micro RNAs (Kretzner et al., 2008). Also alisertib plus romidepsin exhibit highly synergistic effects in lymphoma cell lines (O’Connor, 2012). Thus, this collective data supports the rationale for the evaluation of the combination of romidepsin plus alisertib in patients with multiple lymphoma subtypes.
Methods: Eligible histologies included Hodgkin lymphoma (HL), Burkitt lymphoma (BL), double-hit lymphoma (DHL), other c-Myc positive B-cell lymphomas, diffuse large-B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), or peripheral T-cell lymphoma (PTCL). Patients were treated with alisertib orally on days 1 to 7 and romidepsin IV on days 1 and 8. There are 5 planned escalation dose levels with respective dosing of alisertib plus romidespin of 20 mg BID and 8 mg/m2, 20 mg BID and 10 mg/m2, 40 mg BID and 10 mg/m2, 40 mg BID and 12 mg/m2, and 40 mg BID and 14 mg/m2. Next cycle is given if ANC ≥ 1000 and platelets ≥ 50,000 and maximum cycles is 8. Restaging is done after every 2 cycles with revised response criteria (Cheson et al., 2007). DLT is defined as: 1) grade 4 neutropenia or thrombocytopenia ≥ 14 days and/or 2) grade 3 or 4 non-hematological toxicity attributed to study drugs that could not be controlled by supportive care. Patients with an ANC < 1000 received growth factor support.
A lymph node core biopsy is conducted at baseline and at the end of 1 cycle of therapy, and whole peripheral blood is also collected. Evaluation of intensity of immnohistochemistry (IHC) expression of aurora A kinase will be performed and will be correlated with response, 2. Gene expression profiling (GEP) will be performed and assessments of markers of apoptosis and mitotic catastrophe, 3. GEP of whole peripheral blood will be performed to assess changes beyond those limited to within the tumor that can contribute towards response to therapy.
Results: 9 patients were enrolled and 8 are evaluable for response. The median age was 60 years and histologies were 3 PTCL, 3 DHL defined by FISH, 1 DLBCL with c-Myc translocation by FISH, 1 high-grade (HG) DLBCL, and 1 transformed DLBCL. Median number of prior therapies was 4 (2 to 7) and no patients underwent prior transplant given refractory disease. 3 patients have been enrolled to each of the dose levels 1, 2, and 3. Median number of cycles is 1.5 (1 to 8) with median time for retreatment of 28.5 days (22 to 40). Grade 3/4 toxicities were neutropenia, thrombocytopenia, and anemia in respectively 45%, 45%, and 20% of the cycles. Responses to date are CR (PTCL, dose level 1), SD (PTCL, dose level 3), PD (3 DHL, 1 HG DLBCL, 1 DLBCL with c-Myc, 1 PTCL). 4 of the patients with PD have died from continued refractory disease and 1 has been transitioned to hospice. The CR patient received 7 prior lines of treatment and remains in remission at 5 months in follow-up and declined transplant. The SD patient is now 1 month out from a matched unrelated donor transplant.
Conclusions: Enrollment continues. Based on preclinical data, clinical data for both agents, and responses thus far we plan to consider a dose expansion PTCL patient cohort at the MTD. Reversible cytopenias are the main toxicity to date. We anticipate the correlative studies will allow us to further define the patients with the higher likelihood of having disease response to this targeted therapeutic combination.
Disclosures
Fanale: Seattle Genetics: Consultancy, Honoraria, Research Funding; Millennium/Takeda: Honoraria, Research Funding; Celgene: Research Funding; Novartis: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; MedImmune: Research Funding; Roche: Research Funding; Amgen : DMC, DMC Other. Off Label Use: Will discuss off label use of alisertib plus romidepsin in a phase I trial.. Fowler:Gilead Sciences: Research Funding.
Differential expression of aurora-A kinase in T-cell lymphomas