Combination Trial of Duvelisib (IPI-145) with Bendamustine, Rituximab, or Bendamustine/Rituximab in Patients with Lymphoma or Chronic Lymphocytic Leukemia

Background: Duvelisib, a potent inhibitor of the δ and γ isoforms of phosphoinositide-3-kinase (PI3K) is being developed as a potential therapeutic in hematologic malignancies including chronic lymphocytic leukemia (CLL), as well as B and T cell lymphoma. Single agent bendamustine (B), rituximab (R), and their combination have demonstrated proven activity in iNHL and CLL. Combining duvelisib with bendamustine or rituximab alone or with both drugs may improve response rates and the durability of remission. The primary objective of this trial is to characterize the safety, maximum tolerated dose (MTD), and a preliminary efficacy profile of duvelisib given in combination with rituximab (Arm 1-DR), bendamustine plus rituximab (Arm 2-DBR) or bendamustine (Arm 3-DB) in subjects with select relapsed/refractory lymphoma or CLL.

Methods: Pts with relapsed CLL or NHL, ECOG performance status (PS) ≤2, and adequate organ function were enrolled. The subject population during dose escalation was limited to relapsed NHL. During the dose expansion phase, each treatment arm enrolled to population specific cohorts to continue to assess efficacy. Arm 1 (DR) received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles plus duvelisib PO BID until disease progression or intolerance. Arm 2 (DBR)received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles, bendamustine 90 mg/m2 IV for NHL pts or 70 mg/m2 IV  for CLL pts on Days 1 and 2 of the first six cycles plus duvelisib PO BID until disease progression or intolerance. Arm 3 (DB) received bendamustine 120 mg/m2 IV on Days 1 and 2 of the first six cycles plus duvelisib PO BID up to 12 cycles. Three different dose levels of duvelisib, 25, 50, and 75 mg PO BID were initially explored. Pts were evaluated for response every 3 cycles according to specific criteria for their disease.

Results: Between August 2013 and April 2015, 48 pts, median age 67 yrs (40-83) were enrolled; 12 NHL pts in the dose escalation portion and 36 pts (18 CLL, 18 NHL) in dose expansion.  Pts had a median of 2 prior therapies (1-7).  In arms 1 (DR) and 2 (DBR), no dose limiting toxicities were seen at the highest dose level of duvelisib (75 mg bid). In arm 3 (DB), with a higher  dose of bendamustine, 1 pt developed a DLT at the 50 mg BID dose level of duvelisib (febrile neutropenia, neutropenia ≥ 7 days, thrombocytopenia ≥ 7 days, and liver toxicities which resulted in a treatment delay of ≥ 7 days).  The MTD was not reached in this study but given recent data of single agent duvelisib showing no advantage in doses >25 mg BID, pts on the expansion phase were treated with 25mg BID.  The AE profile of the drug combination is consistent with toxicities of the single agents (Table 1).  There have been 2 potentially treatment-related deaths (cardiac arrest in a pt with history of hypertension and diabetes, and pneumonia), both on Arm 1.  38 pts were evaluable for response with an ORR of 74% (8% CR, 66% PR, 16% SD and 10% PD). The ORR of NHL and CLL pts were 64% and 92% respectively.  With a median follow up of 16.25 mos, median progression free survival is 13.7 mos overall.  Median overall survival (OS) has not been reached, but 15 mo OS probability is 82%.  Pharmacokinetics analysis is consistent with the monotherapy Phase I trial of duvelisib (Figure 2) and is not effected by bendamustine.

Conclusions: Analysis of duvelisib administered in combination with bendamustine and rituximab shows these combinations to be generally well-tolerated with encouraging response.  Further follow-up is required to better characterize both response rates and durability of remissions.

Table 1 Treatment-related AEs (≥15% all pts)     

	ARM 1  (N=28)		ARM 2 (N=18)			ARM 3  (N=2)
Preferred Term	G 1/2	G 3/4		G 1/2	G 3/4	G 1/2	G 3/4	Treated (N=48)
RASH	8 (29%)	3 (11%)		3 (17%)	3 (17%)		0	17 (35%)
DIARRHEA	8 (29%)	3 (11%)		2 (11%)	1 (6%)	1 (50%)	0	15 (31%)
FATIGUE	9 32%)	0		4 (22%)	1 (6%)	1 (50%)	0	15 (31%)
NAUSEA	5 (18%)	0		4 (22%)	0	1 (50%)	0	10 (21%)
ALANINE AMINOTRANSFERASE INCREASED	5 (18%)	1 (4%)		3 (17%)	0	0	0	9 (19%)
NEUTROPENIA	1 (4%)	5 (18%)		0	3 (17%)	0	0	9 (19%)
ASPARTATE AMINOTRANSFERASE INCREASED	4 (14%)	1 (4%)		3 (17%)	0	0	0	8 (17%)
ANAEMIA	3 (11%)	1 (4%)		2 (11%)	0	1 (50%)	0	7 (15%)
PRURITUS	3 (11%)	0		3 (17%)	0	0	0	6 (13%)
UPPER RESPIRATORY TRACT INFECTION	5 (18%)	0		1 (6%)	0	0	0	6 (13%)
CONSTIPATION	4 (14%)	0		1 (6%)	0	0	0	5 (10%)
MUCOSAL INFLAMMATION	3 (11%)	1 (4%)		1 (6%)	0	0	0	5 (10%)

Figure 2 Mean IPI-145 Concentration vs Time Plot with Tx Arms Overlaid for the First 6 Hours (Linear)