Anti-CD79B Antibody-Drug Conjugate DCDS0780A in Patients with B-Cell Non-Hodgkin Lymphoma: Phase 1 Dose-Escalation Study.

PURPOSE: Targeting CD79B using antibody-drug conjugates (ADC) is an effective therapeutic strategy in B-cell non-Hodgkin lymphoma (B-NHL). We investigated DCDS0780A, an anti-CD79B ADC with THIOMAB technology (TDC) that consistently conjugates two anti-neoplastic molecules per antibody, in contrast with ADCs with heterogeneous loads. PATIENTS AND METHODS: This phase 1 study enrolled 60 patients with histologically confirmed B-NHL that had relapsed/failed to respond following ≥1 prior treatment regimens; 41 (68%) had diffuse large B-cell lymphoma (DLBCL). Fifty-one patients received DCDS0780A monotherapy once every 3 weeks (0.3-4.8 mg/kg); 9 received combination therapy (3.6-4.8 mg/kg) with rituximab. RESULTS: Fifty-four (90%) patients experienced adverse events related to study drug, the most common of which were blurred vision, fatigue, corneal deposits, neutropenia, nausea, and peripheral neuropathy. 4.8 mg/kg was the highest dose tested and the recommended phase II dose. The pharmacokinetic profile was linear at doses ≥1.2 mg/kg. Response rate in all-treated patients (N = 60) was 47% (n = 28), including 17 complete responses (28%) and 11 partial responses (18%). The median duration of response (15.2 months) was the same for all responders (n = 28) and patients with DLBCL (n = 20). CONCLUSIONS: DCDS0780A as the TDC format for CD79B was tested at higher doses than its ADC counterpart investigated earlier, leading to deep responses. However, dose intensity was limited by ocular toxicities seen at the higher doses indicating that the TDC format was unable, in the current study, to expand the therapeutic index for the CD79B target. The encouraging antitumor activity advocates continuation of investigations into novel ADC technologies.

Role of pharmacogenetics on adjuvant chemotherapy-induced neutropenia in Chinese breast cancer patients.

BACKGROUND: Breast cancer patients regularly undergo adjuvant chemotherapies following surgery. However, these treatments are largely associated with chemotherapeutic toxicities ranging from nausea to severe myelosuppression. In this investigation, we examined the effects of four SNPs in NR1I2, CYP3A4 and CYP3A5 genes on chemotherapy-induced severe neutropenia in 311 female Chinese breast cancer patients undergoing a standard adjuvant chemotherapy regimen. METHODS: Patients were monitored for adverse reactions throughout the treatment, then divided into "none or mild" (80 %) or "severe" (20 %) toxicity groups according to whether they suffered grade 4 neutropenia defined as having an absolute neutrophil counts (ANC) of less than 0.5 × 10(9)/L anytime during the treatment. DNA was extracted from patients' peripheral blood samples, then genotyped using allele-specific Tm-shift PCR and melting analysis. RESULTS: Logistic regression revealed that rs776746 or CYP3A5*3 strongly associated with grade 4 neutropenia (OR = 2.56, P = 0.023) after adjustment for covariates, one of which more significant factor was baseline ANC (OR = 0.68, P = 0.020). Although univariate analysis in all patients did not reveal any association at first, further analysis indicated that rs776746 is significantly associated with severe neutropenia in subgroup of breast cancer patients with normal baseline ANC (≥2.0 × 10(9)/L). These carriers of A-allele have 3.14-fold increased risk of developing severe neutropenia (P = 0.004). CONCLUSION: Our results suggested that polymorphisms in CYP3A5 might be useful pharmacogenetic markers for the prediction of severe neutropenia during chemotherapy, however, only after screening patients by their baseline ANC in the presence of gene-environmental interaction. We demonstrate an approach of pharmacogenetic analysis, in which the genetic data should be analyzed in the perspective of other clinical parameters.