sapacitabine (CYC682)

Sapa/ola produces high rates of hematologic toxicity. However, the ORR of 50%, mPFS of 9.7 months, and durability of 3+ years in 2 pts suggest possible combinatorial benefit. Further exploration with different sapa schedules or with substitution of a PARP1-selective inhibitor to decrease hematologic toxicity is warranted.

P1, N=10, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | Phase classification: P1/2 --> P1 | N=64 --> 10

P1, N=103, Completed, Cyclacel Pharmaceuticals, Inc. | Recruiting --> Completed

Previous studies of sapacitabine alone and alternating with decitabine (DAC) have demonstrated activity in acute myeloid leukemia (AML). In a heavily pretreated population of patients with R/R AML, the combination of sapacitabine and VEN was well tolerated and feasible to be administered as a completely oral, outpatient regimen. Most patients had multiple prior cycles of nucleoside analogue containing regimens and the only notable responder had only prior DAC. Further study of this well-tolerated combination in less heavily pretreated patients may be considered.

Treatments included: Low dose Ara-C (LDAC) alone, sapacitabine alone and LDAC in combination with vosaroxin, tosedostat or ganetespib (MRC/NCRI); Azacytidine (AZA) alone, tipifarnib alone, and AZA in combination with mylotarg, midostaurin, and nivolumab (SWOG). Our ability to predict early death in older patients treated with lower intensity AML therapies is limited with routinely available clinical variables. Inclusion of cytogenetic risk, FLT3-ITD, and NPM1 mutation status minimally improved the prognostic accuracy as did some of the QLQ-C30 subscales. Our data highlight the difficulties in predicting outcomes with non-intensive AML therapy with routinely available baseline clinical information.

Intrinsic and acquired resistance to CNDAC and related nucleoside analogues are driven by different mechanisms. The lack of cross-resistance between SAMHD1/ DCK substrates and non-substrates provides scope for next-line therapies after treatment failure.

P1/2, N=64, Recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Jun 2020 --> Jun 2022

ATRX LoF results in specific DNA damage repair defects that can be therapeutically exploited. In ATRX LoF models, preclinical sensitivity is demonstrated to olaparib and irinotecan, a combination that can be rapidly translated into the clinic.

Cytarabine (Ara-C) is the most active drug against AML; azacitidine and decitabine are active treatments of myelodysplastic syndrome (MDS) and AML...The combination of CNDAC (2’-C-cyano-2’-deoxy-1-β-D-arabino-pentafuranosylcytosine), the active metabolite of sapacitabine, and BCL2 inhibitor ABT737 was studied in AML cell line MV-411...Treatment will continue until progression of disease, unacceptable toxicity or changes in patient condition that renders patients ineligible for further treatment. Laboratory tests and bone marrow aspirate/biopsy will be performed to assess responses according to standard criteria.