Multiarm Phase I study of the cyclin dependent kinase (CDK4/6) inhibitor palbociclib in combination for patients with relapsed and refractory acute leukemias Free

Background Cyclin-dependent kinases (CDKs) are key regulators of cell cycle progression in proliferating cells and are commonly dysregulated in acute leukemias. Inactivation of p16 or p15, leading to over-activity of CDK4/6 is described in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). CyclinD-CDK4/6 axis is a downstream effector of FLT3 signaling and CDK6 has been shown to a be direct target of KMT2a fusion proteins, implicated in driving KMT2a-rearranged AML by inhibiting myeloid differentiation. RNAi screen as well as CDK4/6 inhibitor in KMT2a cell lines led to growth arrest and differentiation.

Methods This is an investigator-initiated phase I trial studying the safety of the CDK4/6 inhibitor palbociclib (palbo) alone (cycle 1) and then in various combinations (cycle 2+). Patients (pts)>15 yrs, with R/R AML or R/R ALL and adequate organ function were eligible. Four combination arms were studied (in a 28-day cycle): (A) sorafenib 400mg PO BID on D1-28; (B) decitabine 20 mg/m² IV on D8-17; (C) dexamethasone 40mg on D1-4 & 11-14, and (D) Venetoclax 400 mg on D1-21. Pts were assigned to an arm at enrollment by physician choice; only R/R ALL pts were eligible for arm C. During cycle 1 all pts received palbo 125mg PO on D1-28. Starting cycle 2, pts continued palbo (D1-28) with their assigned combination (A,C, or D). Pts in cohort B received palbo D1-7 per cycle.

Results Thirty-one pts with R/R AML or ALL with a median of 4 (range, 1-11) prior therapies have been enrolled: 28 (90%) with AML, 1 (3%) with B-ALL, 1 (3%) with T-ALL, and 1 (3%) with mixed phenotype acute leukemia. The median age was 61 yrs (16-86) and pts received a median of 2 (1-5) cycles of therapy on protocol. Eight pts (26%) had received prior SCT. Pts with AML had the following karyotypes: Diploid (3, 10%), Complex (14, 45%), Intermediate (1, 3%) Adverse (10, 23%). Five pts (16%) had KMT2a-r and 1 (3%) had MECOM-r. The most frequently encountered mutations in AML pts were TP53 (26%), WT1 (22%), ASXL1 (19%), and RUNX1 (15%). Two pts with FLT3-ITD^mut were treated on arm A with sorafenib.

Single-agent palbo during cycle 1 was well tolerated. All pts had myelosuppression related to their disease. Drug-related non-hematologic adverse events (AEs) included fatigue, diarrhea, and nausea, all grade 1-2. One pt experienced grade 2 hand-foot syndrome possibly related to palbo. The most common non-hematologic AEs on trial, regardless of attribution, included febrile neutropenia (3%), lung infection (3%) and diarrhea (3%). The incidence of Grade >3 AEs was 18%, including febrile neutropenia (3%) and lung infection (2.7%). The 4-week mortality was 6.5%. Fourteen pts (45%) had progressive disease or died prior to cycle 2; 7, 17, 2, and 5 were planned for arm A, B, C, and D, respectively. Of the 17 pts (55%) who proceeded to the combination cycle, 3 (18%) went on arm A, 10 (59%) on arm B, and 2 (12%) each went on to arms C and D. No DLTs have been observed.

Of the 3 pts on arm A, 1 (33%) with co-occurring FLT3-ITD and -TKD^muthad stabilization/improvement in peripheral blasts and 1 FLT3^wt pt (33%) had reduction in bone marrow (BM) blasts (from 68% to 36%). Three (30%) of the 10 pts on arm B had reduction in BM blasts (of which 1 had >50% reduction), and 5 (50%) had stabilization/improvement in peripheral blasts. One pt (50%) who proceeded to arm C had improvement in extramedullary T-ALL and 1 (50%) who proceeded to arm D had stabilization of BM blasts for several cycles.

For the 5 pts with KMT2Ar, 2 (40%) went beyond cycle 1 to receive combination therapy; 1 (20%) on arm B experienced stabilization/improvement in peripheral blasts. All 3 pediatric pts had AML, of which 2 were in cohort B and 1 was in cohort D; 2 (67%) had evidence of clinical benefit with 1 in cohort B experiencing a reduction in BM blasts (from 90% to 60%) and 1 in cohort D experiencing stabilization of BM blasts for 5 cycles.

The median OS for all pts was 3 months (95% CI 1.9 – 6.1). The median OS for cohort A vs. B vs. C vs. D was 2.1 months vs. 3.3 months vs. 11.5 months vs. 1.6 months (p=0.18).

Conclusion In our cohort of heavily pre-treated, high-risk pts, treatment with palbo was tolerated without unexpected toxicity. While no complete remissions were observed, clinical benefit was noted in several pts, particularly in combination with HMA. Further evaluation of palbo, especially in earlier lines of therapy and in combinations for KMT2a-r or FLT3^mutAML may be warranted.