This is a phase I study of the combination of volasertib and romidepsin in patients with relapsed/refractory peripheral T cell lymphoma (PTCL) or stage IIB-IV cutaneous T cell lymphoma (CTCL). This study will determine the maximum tolerated dose (MTD) of this combination by treating cohorts of patients at a certain dose combination. The investigators will use a Bayesian design to determine the dose combination for the next cohort of patients and to determine the MTD. Overall response rate as well as adverse events will be monitored and reported.
This is a non-randomized, unblinded single arm Phase I multi-center trial to determine the maximum tolerated dose (MTD) of the combination of volasertib and romidepsin in patients with relapsed/refractory peripheral T cell (PTCL) and cutaneous T cell (CTCL) lymphoma. Primary Objectives: 1\. Determine the maximum tolerated dose (MTD) of the combination of romidepsin and volasertib in patients with relapsed/refractory peripheral T cell and cutaneous T cell lymphoma. Secondary Objectives: 1. Evaluate the overall response rate (ORR) to the combination of romidepsin and volasertib in patients with relapsed/refractory peripheral T cell and cutaneous t cell lymphoma. 2. Define gene expression signatures and patterns of acquired tumor mutations that dynamically correlate to clinical response to romidepsin/volasertib combination therapy in cutaneous T cell lymphoma (CTCL) through longitudinal RNA sequencing of tumor samples. Dose Combinations (-1): Volasertib 50mg/m2 Days 1 \& 8; Romidepsin 10mg/m2 Days 1, 8 \& 15 (1-starting dose): Volasertib 75mg/m2 Days 1 \& 8; Romidepsin 12mg/m2 Days 1, 8 \& 15 (2): Volasertib 100mg/m2 Days 1 \& 8; Romidepsin 12mg/m2 Days 1, 8 and 15 (3): Volasertib 100mg/m2 Days 1 \& 8; Romidepsin 14mg/m2 Days 1, 8 and 15 (4): Volasertib 150mg/m2 Days 1 \& 8; Romidepsin 14mg/m2 Days 1, 8 and 15 Each cycle is 28 days Each drug is given intravenously
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Volasertib 75-150mg/m2 given intravenously on days 1 and 8
Romidepsin 12-14mg/m2 given intravenously on days 1, 8 and 15
Maximum Tolerated Dose
Determine the maximum tolerated dose (MTD) of the combination of romidepsin and volasertib in patients with relapsed/refractory peripheral T cell and cutaneous T cell lymphoma.
Time frame: 12 months or until 2 DLTs are experienced in a cohort
Overall Response Rate
Evaluate the overall response rate (ORR) to the combination of romidepsin and volasertib in patients with relapsed/refractory peripheral T cell and cutaneous t cell lymphoma.
Time frame: 24 months
Gene Expression Signature
Define 1) genes expressed at significantly different levels (using linear analysis or the Wilxocon rank sum test and p\< 0.05 as significance threshold) in tumor biopsies taken before treatment from patients exhibiting a clinical response versus non-responders to romidepsin/volasertib by analysis of levels of mRNA gene transcription by mRNA whole transcriptome sequencing (RNA-seq) Comparison of baseline to interim 8 week biopsy samples will be used to define changes in gene expression induced by combination treatment. These will be derived for each patient by using paired T tests for RNA sequencing FPKM values with correction for multiple comparisons via FDR calculation by the Benjamini-Hochberg method (a cutoff of FDR \< 0.05 will be used to define genes included in the treatment gene signature).
Time frame: 60 months
Gene Mutation Analysis
Define 2) and 2) define mutations associated with primary (lack of clinical response) or acquired resistance (relapse or loss of response after first clinical response) to romidepsin/volasertib by analysis of tumor genetic sequences by using RNA-seq metholodies on tumor samples taken before or after treatment with romidepsin/volasertib and analysis of paired normal DNA sequence(s). Mutations for relapse samples will be obtained by comparing transcriptome profiles before and after development of resistance to romidepsin/volasertib. Specifically, we will assess whether individual genes become mutated at relapsed in a recurrent fashion (in 2 or more patients in the cohort).
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Time frame: 60 months