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Combinations of epigenetic modifiers, such as romidepsin and azacytidine (or decitabine), romidepsin and the antimetabolite pralatrexate (which in preliminary data showed immunomodulatory activity affecting genes involved in hypomethylation), or pralatrexate and decitabine showed a synergistic effect in early phase clinical studies on peripheral T-cell lymphomas (PTCLs).
At the American Association for Cancer Research (AACR) Meeting I, Enrica Marchi presented preliminary results of the EMBOLDEN and DURABILITY phase I studies, evaluating the combination of immune-checkpoint inhibitors with epigenetic therapy in patients with T-cell lymphoma. To watch Enrica Marchi discuss it click here.
This multicentre, multi-arm, international, phase Ib dose-escalation study (NCT03240211) evaluated the combination of the PD1 inhibitor pembrolizumab with pralatrexate, with pralatrexate and decitabine, or with decitabine. The phase I part of the study enrolled 13 patients with relapsed/refractory PTCL and cutaneous T-cell lymphoma (CTCL):
The primary objectives were to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and dose-limiting toxicity (DLT) of various combinations of pembrolizumab, pralatrexate, and decitabine. This phase will be followed by an expansion phase.
The majority of patients enrolled had a histology of PTCL, not otherwise specified (NOS) and entered the study with advanced-stage disease. Patient characteristics are reported in Table 1.
Table 1. Patient characteristics in the EMBOLDEN trial1
AITL, angioimmunoblastic T-cell lymphoma; ATLL, adult T-cell leukemia/lymphoma; PTCL-NOS, peripheral T-cell lymphoma, not otherwise specified |
|
Characteristic |
Patients (N = 13) |
Median age, years (range) |
66 (38–77) |
Histology, n (%) PTCL-NOS AITL Mycosis fungoides ATLL Sezary syndrome |
6 (46) 3 (23) 2 (15) 1 (8) 1 (8) |
Stage at diagnosis IB II III IV Tumor stage |
1 (8) 1 (8) 5 (38) 5 (38) 1 (8) |
Median number of prior therapies (range) |
2 (1–5 ) |
Table 2. Patient outcomes in the EMBOLDEN trial1
CR, complete response; ORR, overall response rate; POD, progression of disease; PR, partial response; SD, stable disease |
|
Parameter |
Number of patients (N = 13) |
ORR |
2 |
CR |
1 |
PR |
1 |
SD |
1 |
POD |
3 |
This open-label, multi-arm, phase I/IIa study (NCT03161223) is evaluating the combination of the PD-L1 inhibitor durvalumab with different epigenetic modifiers in patients with PTCL with relapsed/refractory or de novo disease. The initial phase I dose-finding portion of the study enrolled five patients and comprises four arms (every cycle is 28 days):
Primary objectives of this phase are MTD, RP2D, and DLT of the different combinations. The phase I part of the study will be followed by phase II once the RP2D is identified.
The majority of patients enrolled had a histology of PTCL-NOS; patient characteristics are reported in Table 3.
Table 3. Patient characteristics in the DURABILITY trial1
AITL, angioimmunoblastic T-cell lymphoma; ALCL ALK+, anaplastic large cell lymphoma anaplastic lymphoma kinase-positive; PTCL-NOS, peripheral T-cell lymphoma, not otherwise specified; TFH, T-follicular helper |
|
Characteristic
|
Patients (N = 5) |
Median age, years (range) |
44 (26–76) |
Histology, n (%) PTCL-NOS PTCL-NOS TFH AITL ALCL ALK+ |
2 (40) 1 (20) 1 (20) 1 (20) |
Stage at diagnosis II III IV Unknown |
1 (20) 2 (40) 1 (20) 1 (20) |
Median number of prior therapies (range) |
2 (0–4) |
Table 4. Patient outcomes in the DURABILITY trial1
CR, complete response; ORR, overall response rate; POD, progression of disease; PR, partial response; SD, stable disease |
|
Parameter |
Number of patients (N = 5) |
ORR |
3 |
CR |
3 |
PR |
0 |
SD |
0 |
POD |
0 |
These preliminary results suggest that the combination of immune-checkpoint inhibitors and epigenetic modifiers is well tolerated. Encouraging responses were observed, with no hyperprogressive disease in patients with PTCL and CTCL.
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