Alisertib and romidepsin combination for aggressive R/R T-cell and B-cell lymphomas

On 9 May 2019, Paolo Strati from the MD Anderson Cancer Center, Houston, TX, USA, and colleagues, published in Haematologica¹ results from a phase I clinical trial, investigating the safety and tolerability of alisertib and romidepsin in aggressive B-cell and T-cell lymphomas.

Alisertib is an aurora A kinase inhibitor, which exerts its function by disrupting tumor cell division. Pre-clinical and phase II studies have indicated alisertib’s anti-tumor activity against various haematological malignancies, including B-cell and T-cell non-Hodgkin lymphomas.^2,3 Romidepsin, a class I histone deacetylase inhibitor induces cell cycle arrest and has been approved by the Food and Drug Association for the treatment of relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL).

In this open-label, single-center, phase I trial (NCT01897012), patients with aggressive R/R B-cell or T-cell lymphoma were treated with alisertib and romidepsin combination. The primary endpoint of the study was toassess the safety profile of the combination treatment and to determine the the maximum tolerated dose (MTD). Secondary endpoints included overall response rate (ORR) and complete response (CR) rate.

Study design & baseline characteristics

• N = 25 patients aged ≥ 18 years with histologically-confirmed, R/R B-cell or T-cell lymphoma with at least one measurable disease site ≥5 cm, Eastern Cooperative Group (ECOG) performance status ≤ 2
• Patient diagnosis:
  • Diffuse large B-cell lymphoma (DLBCL): 48% (n = 12)
  • Hodgkin lymphoma (HL): 28% (n = 7)
  • PTCL: 16% (n = 4)
  • Burkitt lymphoma (BL): 8% (n = 2)
• Patients with low grade B-cell lymphoma or central nervous system involvement were excluded
• Median age (range): 56 (23–77) years
• Median number of previous lines (range): 4 (1–10)
• Patients who had relapsed < 6 months before study initiation: 92% (n = 23)
• Romidepsin was administered intravenously and alisertib orally twice a day (BID), at eight dose levels, as below:

Dose level (DL)	Time between treatment cycles	Alisertib		Romidepsin
		Dose	Cycle days	Dose	Cycle days
Level 1 (n = 3)	21 days	20 mg BID	1–7	8 mg/m2	1,8
Level 2 (n = 3)	21 days	20 mg BID	1–7	10 mg/m2	1,8
Level 3 (n = 3)	21 days	40 mg BID	1–7	10 mg/m2	1,8
Level 4 (n = 3)	21 days	40 mg BID	1–7	12 mg/m2	1,8
Level 5 (n = 3)	28 days	20 mg BID	1–3; 8–10; 15–17	10 mg/m2	2, 9, 16
Level 6 (n = 3)	28 days	30 mg BID	1–3; 8–10; 15–17	10 mg/m2	2, 9, 16
Level 7 (n = 3)	28 days	30 mg BID	1–3; 8–10; 15–17	12 mg/m2	2, 9, 16
Level 8 (n = 3)	28 days	40 mg BID	1–3; 8–10; 15–17	12 mg/m2	2, 9, 16

• Dose limiting toxicity (DLT) was assessed during Cycle 1:
  • Non-hematological DLT: Any Grade 3–4 non-manageable toxicity due to study drugs
  • Hematological DLT: Grade 4 neutropenia or thrombocytopenia lasting > 14 days
• Standard ‘3 + 3’ study design for MTD determination
• Response assessment was performed at the end of all even numbered cycles
• Median time on study (range): 2 (1–8) months

Key findings

Safety & tolerability

• Median number of delivered treatment cycles (range): 2 (1–8) months
• Median interval between cycles (range): 4 (3–9) weeks
• Number of patients discontinuing treatment: 96% (n = 24), due to:
  • Disease progression (PD): 79% (n = 19)
  • Treatment completion: 9% (n = 2)
  • Indication for stem cell transplantation (SCT): 4% (n = 1)
  • Patient choice: 4% (n = 1)
  • Toxicity: 4% (n = 1; atrial fibrillation)
• No DLTs were observed
• Most common Grade ≥ 3 hematological adverse events (AEs) were:
  • Thrombocytopenia: 40% (n = 10)
  • Anemia: 28% (n = 7)
  • Neutropenia: 24% (n = 6)
  • Deep vein thrombosis/pulmonary embolism: 8% (n = 2)
  • Febrile neutropenia: 4% (n = 1)

Efficacy (n = 24 evaluable patients)

• ORR (total cohort): 28% (n = 7/25; intention-to-treat [ITT] analysis)
• ORR (HL cohort): 71% (n = 5/7)
• Patients who achieved CR: 12% (n = 3; HL, n = 2 and mycosis fungoides, n = 1)
• Patients who achieved PR: 16% (n = 4; DLBCL, n = 1 and HL, n = 3)
• Patients with stable disease: 20% (n = 5)
• After a median follow-up of 5 months (range, 1–46):
  • Patients with PD: 92% (n = 23; one progressed after allogeneic SCT)
  • PFS > 6 months was observed in n = 5 patients (HL, n = 2; PTCL, n = 2; DLBCL, n = 1)
• At the latest follow-up (data cut off: January 2018) median OS was 12 months (range, 1–46) with 44% (n = 11) of patients having died due to PD

Conclusions

Although the combination of alisertib and romidepsin followed an expected safety profile with no observed DLTs, the preliminary efficacy of the treatment was low in this heavily pre-treated patient population with R/R T-cell or B-cell lymphomas (ORR: 28%) with the exception of patients with HL (ORR: 71%)