AACR 2020 | Preliminary results of the EMBOLDEN and DURABILITY phase I studies on the combination of immune checkpoint inhibitors with epigenetic therapy in patients with T-cell lymphoma

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.

EMBOLDEN trial

Study design and patient characteristics

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):

• Arm A
  • Pralatrexate de-escalating dose (20–30 mg/m² intravenously [IV]) on Days 1, 8, 15
  • Pembrolizumab flat dose (200 mg IV) on Day 1
• Arm B
  • Pralatrexate escalating dose (20–30 mg/m² IV) on Days 1, 8, 15
  • Decitabine escalating dose (10–20 mg/m²) on Days 1–5
  • Pembrolizumab flat dose (200 mg IV) on Day 8
• Arm C
  • Decitabine de-escalating dose (10–20 mg/m²) on Days 1–5
  • Pembrolizumab flat dose (200 mg IV) on Day 8

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 )

 Results

Safety

• In terms of toxicities, the most common Grade 3/4 adverse event (AE) observed was thrombocytopenia (n = 3; 23%). Other AEs (occurring in one patient each) included neutropenia, fatigue, vomiting, immune-related AE, hyponatremia, and rash
• A DLT was observed for each arm, including prolonged Grade 3 thrombocytopenia, febrile neutropenia, Grade 3 hyponatremia, and rash

Efficacy

• There were 6/13 patients evaluable for response and all the responders were in Arm B. After 18 months, the partial response is still ongoing. The outcomes are reported in Table 2.

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

 DURABILITY trial

Study design and patient characteristics

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):

• Arm A
  • Azacytidine (300 mg orally) on Days 1–14
  • Romidepsin (12 mg/m²) on Days 8 and 15
  • Durvalumab (1,500 mg IV) on Day 8
• Arm B
  • Pralatrexate (25 mg/m² IV) on Days 1 and 15
  • Romidepsin (12 mg/m² IV) on Days 1 and 15
  • Durvalumab (1,500 mg IV) on Day 1
• Arm C
  • Romidepsin (12 mg/m² IV) on Days 1, 8, and 15
  • Durvalumab (1,500 mg IV) on Day 1
• Arm D
  • Azacitidine (300 mg orally) on Days 1–Day 14
  • Durvalumab (1,500 mg IV) on Day 8

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)

 Results

Safety

• Grade 3/4 AEs observed were thrombocytopenia (n = 2; 40%), lymphopenia (n = 2; 40%), and cytokine release syndrome (n = 1; 20%)
• A DLT of cytokine release syndrome was observed in Arm A  

Efficacy

• There were 3/5 patients evaluable for response and all the responders were in Arm A. The outcomes are reported in Table 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

 Conclusion

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.