Early Results Show Palbociclib Helps Sustain Patient Response to Ibrutinib in MCL

Surabhi Dangi-Garimella, PhD

While ibrutinib as a single agent is not very effective in maintaining a durable response in patients with mantle cell lymphoma (MCL), early phase 1 results now show that including the cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib in the treatment plan can help overcome resistance to ibrutinib. The results were presented by Peter Martin, MD, associate professor of Medicine at Weill Cornell Medical College, Cornell University, during the 58th American Society of Hematology Annual Meeting & Exposition, being held December 3-6, in San Diego, California.
 
“About one-third patients on ibrutinib do not respond to the drug, and so combination treatments are warranted,” Martin said. Previous studies by our group—in cell lines expressing wild-type Bruton tyrosine kinase (BTK) and in primary human samples—showed that treatment with the G1-specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance,1 Martin told the audience. “We found that prolonged cell cycle arrest could sensitize cells to death by a PI3K or BTK inhibitor.”

The current phase 1 trial was designed based on the in vitro observations, to evaluate the safety and preliminary activity of palbociclib plus ibrutinib in patients with previously treated MCL.2 The primary objective of the trial was to select the recommended phase 2 dose for the combination of ibrutinib and palbociclib, with secondary objectives of characterizing the toxicity profile and estimating the objective response rate (ORR), the complete response (CR), and progression-free survival (PFS).
 
The primary eligibility criteria for trial enrollment, Martin said, were adults who were previously treated for MCL, without receiving treatment with CDK4/6 or BTK inhibitors. Further, patients should have had acceptable marrow and organ function. The median age of the 23 enrolled patients was 65 years (range 42-81), and a majority were male. Fourteen of the 23 had received prior autologous stem cell transplant. The following doses of the 2 drugs were used:
 
Table 1. Doses of Ibrutinib and Palbociclib Administered to Patients in the Trial
Dose level Ibrutinib (daily) Palbociclib (days 1 to 21/28)
1 280 mg 75 mg
2 420 mg 75 mg
3 420 mg 100 mg
4 580 mg 100 mg
5 580 mg 125 mg
 
Patients were treated in 28-day cycles—ibrutinib was administered daily and palbociclib was administered on days 1 to 21 (Table 1), and treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Patients were evaluated for efficacy at the end of cycles 3 and 6, and every 6 cycles thereafter. Computed tomography (CT) was used to monitor patient response to treatment and confirmed by positron emission tomography/CT.

The following table lists the toxicities that were observed:

Table 2. Treatment-associated toxicities.
Grade Toxicity
3/4 hematological toxicity Thromocytopenia (28%)
Neutropenia (22%)
Lymphopenia (17%)
3/4 non-hematological toxicity Lung infection
Encephalitis
Hyponatremia
Sinus tachycardia
Pneumonitis
Increased ALT/AST
1/2 adverse events Diarrhea (50%)
Fatigue (44%)
Rash (39%)
Bruising (17%)
Nausea (17%)
Fever (11%)
Dyspepsia (11%)
Myalgia (11%)
ALT indicates alanine transaminase; AST, aspartate transaminase.
 
Two patients experienced grade 3 rash at dose level 5, and were the only ones that required dose reductions; 6 patients required dose interruptions. Thirteen patients continued participating in the trial, while 4 dropped out due to disease progression, 2 due to adverse event, and 1 to undergo allogeneic stem cell transplantation. Dose-limiting toxicities established dose level 4 (ibrutinib 560 mg daily and palbociclib 100 mg x 21/28 days) as the maximum tolerated dose for further studies, Martin said.

Overall, 19 of 21 patients had a response to treatment, with 9 achieving a CR: 3 at dose level 1, 1 at dose level 2, and 2 at dose level 3. A partial response was observed in 4 patients, 1 each at doses levels 2 and 4 and 2 at dose level 3.

The ORR was 64% and CR rate 43%, with a median time to CR of 3 months. The estimated 1-year PFS was 61% and only 1 patient had disease progression.

Martin concluded that the mechanism-based combination of ibrutinib plus palbociclib was well tolerated in their study and showed activity. Biomarker studies to evaluate mechanisms of primary resistance are ongoing and a phase 2 multi-center study to evaluate time to progression is planned, he added. “As is usually seen, patients whose disease progresses seem to do so early, and when they progress, they have poorer outcomes.”
 
Reference
1. Chiron D, Di Liberto M, Martin P, et al. Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 2014;4(9):1022-1035. doi: 10.1158/2159-8290.CD-14-0098.
2. Martin P, Blum K, Bartlett NL, et al.  A phase I trial of ibrutinib plus palbociclib in patients with previously treated mantle cell lymphoma. Presented at the 58th American Society of Hematology Annual Meeting & Exposition, December 3. Abstract 150. 
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