Phase Ib/II study of safety and efficacy of low-dose decitabine-primed chemoimmunotherapy in patients with drug-resistant relapsed/refractory alimentary tract cancer

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Summary

The study investigates a phase Ib/II trial evaluating low-dose decitabine-primed chemoimmunotherapy in patients with drug-resistant relapsed/refractory (R/R) esophageal, gastric or colorectal cancers. The safety and efficacy of decitabine-primed re-sensitization to chemoimmunotherapy is promising. These data warrant further large-scale evaluation of drug-resistant R/R AT cancer patients with advanced stage disease.

Patients characteristics

48 patients with relapsed or refractory esophageal cancer (EC) n=16, gastric cancer (GC) n=17 and colorectal cancer (CRC) n=15 aged 18 to 85 years with histologically confirmed stage III to IV disease, documented drug resistant to chemotherapy/CIK cell treatment (defined as relapsed [disease recurring within 6 months after original therapy] or refractory [disease progression while receiving or persistent disease after original therapy]), Eastern Cooperative Oncologic Group (ECOG) performance status of 0 to 2 and adequate bone marrow, cardiac, renal and liver functions.
Patients were assigned to one of the two treatment cohorts according to the treatment history (whether CIK cell treatment was used before enrollment) and for patients in the decitabine-primed chemotherapy cohort (D-C cohort).

Methodology

CIK cell culture
CIK cells were isolated by standard Ficoll separation and then cultured with CIK cell medium supplemented with 0.6% autogeneic serum. The growth medium was supplemented with 1000 U/ml recombinant human interferon (IFN)-g, 1000 U/ml recombinant human interleukin (IL)-2 (rhIL-2) and 5 lg/ml anti-CD3 antibody on day 0. Every 3 days, fresh CIK cell medium and 1000 U/ml rhIL-2 were added. After 14-days of culture, CIK cells were harvested with a survival rate of > 95%.

Treatment

For patients in the decitabine-primed chemotherapy. Decitabine was administered to all patients at 7 mg/m /d intravenously (IV) on days 1 to 5 of each 28-day treatment cycle. The corresponding resistant first-line chemotherapy was subsequently given on days 6 and 7.
For the D-C and CIK cell treatment cohort (D-C-CIK cell cohort), patients received the above-mentioned regimen, followed by CIK cells administration on days 14 and 15 in a 28-day cycle. Treatment duration was up to 16 months or until progressive disease (PD) or unacceptable adverse events (AEs) occurred or upon patient request to discontinue therapy.
The CIK cell transfusion was performed intravenously with 1.0–5.0×109 CIK cells per infusion (one transfusion per day for 2 days). After each CIK cell transfusion, the patients were injected subcutaneously with 2 mU rhIL-2 each day for 7 consecutive.

Results

Safety
None of the 45 patients withdrew from the treatment because of AEs or experienced treatment-related death. In the overall population, the most frequently observed treatment-related AEs were fatigue (n=45, 100%), anorexia (n=24, 53.3%), anemia (n=24, 53.3%) and leukopenia (n=23, 51.1%). Grade 3–4 treatment AEs occurred in 11 of 45 patients (24.4%) and included leukopenia (n=10, 22.2%), neutropenia (n=10, 22.2%), thrombocytopenia (n=3, 6.7%), anemia (n=1, 2.2%), nausea (n=1, 2.2%) and diarrhea (n=1, 2.2%). These AEs were easily medically managed if the chemotherapy doses were reduced by 20% of the therapeutic doses of the standard chemotherapy regimens. Several expected chemotherapy-related AEs, such as fatigue (n=45, 100%), alopecia (n=23, 51.1%) and anorexia (n=37, 82.2%). EC and GC groups experienced higher rates of any-grade and grades 3 and 4 hematologic toxicities than the CRC group.
Efficacy
In the overall population, 2 (4.44%) patients achieved complete response (CR), 9 (20%) had partial response (PR) and 26 (57.78%) experienced stable disease (SD). The ORR and DCR were 24.44% (95% CI, 11.89 to 37.00) and 82.22% (95% CI, 71.05 to 93.39), respectively. PD was infrequent, with 8 (17.78%) patients having PD as their BOR per RECIST v1.1.
Of the 25 patients in the D-C-CIK cell cohort, 1 (4%) had CR, 6 (24%) had PR and 16 (64%) had SD, for an ORR of 28% (95% CI, 12.07 to 49.39) and DCR of 92% (95% CI, 73.97 to 99.02).
Of the 20 patients with the D-C regimen, 1 (5%) had CR, 3 (15%) had PR and 10 (50%) had SD, for an ORR of 20% (95% CI, 5.73 to 43.66) and DCR of 70% (95% CI, 45.72 to 88.11).
Eleven (24.44%) patients achieved the objective clinical response per RECIST v1.1, with 6 (6 of 15, 40%) with EC, 4 (4 of 16, 25%) with GC and 1 (1 of 14, 7.1%) with CRC. The DCR of the separate cancer types were 86.67%, 87.50% and 71.43%, respectively.
Survival
For all the 45 patients who completed at least two cycles of epigenetic primed chemoimmunotherapy, the median PFS and OS were 5 (95% CI, 4–6 months) and 12 months (95% CI, 9–13 months), comparing favorably with the best PFS before resistance to the corresponding chemoimmunotherapy regimens. The 6- month PFS and 1-year OS rates of the D-C-CIK cell cohort were 37.89% and 32%, respectively. For patients with D-C treatment, the 6-month PFS and 1-year OS rates were 30% and 45%, respectively. Across the three groups of cancer type, the 6-month PFS and 1-year OS rates ranged from 26.7% to 43.75% and 31.25% to 42.86%, respectively.

Conclusion

The safety and efficacy of decitabine-primed re-sensitization to chemoimmunotherapy is attractive and promising. These data warrant further large-scale evaluation of drug-resistant R/R AT cancer patients with advanced stage disease.

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Scientific article publishing date 4/16/2018

Immucura identifier BSC21_295EN

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