Faculty Bibliography

Background: Based on early evidence of cumulative toxicity of PoV at a dose of 2.4 mg/kg (Morschhauser ASH 2014; NCT01691898), a dose of 1.8 mg/kg dose was explored. Aims: To report updated results of the dose comparison. Safety and efficacy of PoV after 8 treatment cycles were also analyzed. Methods: Patients (pts) with R/R FL received PoV at 2.4 mg/kg or 1.8 mg/kg with R 375mg/m², q21d until progression or unacceptable toxicity. Five pts with R/R FL from the Phase 1 study (Palanca-Wessels ASH 2013) treated with PoV 2.4 mg/kg were included in the analysis. Data at completion of PoV treatment were compared with data after 8 cycles. Results: Forty-five pts received PoV+R (25, 2.4 mg/kg; 20, 1.8 mg/kg). Median follow-up was 14 mo. for 2.4 mg/kg vs 8 mo. for 1.8 mg/kg. When limited to the first 8 treatment cycles, median follow-up was similar at 6 mo. for both groups. Baseline characteristics were balanced between the two cohorts, except for age (median 68 yrs 2.4 mg/kg, 62 yrs 1.8 mg/kg) and tumor volume (SPD 1824 mm² at 2.4 mg/kg, 2655mm² at 1.8 mg/kg). Overall, 40% (10/25, 2.4 mg/kg) and 50% (10/20, 1.8 mg/kg) of pts were refractory to their last treatment. At data cut-off for this analysis, pts received a median of 10 and 9.5 treatment cycles in the 2.4 mg/kg and 1.8 mg/kg groups, respectively, with median dose intensities after cycle 8 of 88% and 99%, respectively. Safety is shown in the Table 1. Peripheral neuropathy (PN) was more frequent with PoV 2.4 mg/kg, and discontinuation (d/c) rates due to all causes were 56% vs 30% with the 1.8 mg/kg dose. After 8 treatment cycles, d/c rates were similar for both doses (28% vs 25%). An 84-year old pt in the 2.4 mg/kg cohort died 2 mo. after cycle 12 due to pulmonary congestion. (Table Presented) Summary and Conclusions: PoV+R in R/R FL showed high ORR at both doses, with higher CR at 2.4 mg/kg. D/c rates, mostly due to cumulative PN, were high. AEs and d/c rates were reduced at both doses if only the first 8 cycles are considered vs those reported through study completion. The safety of PoV can be improved by shorter treatment and/or lower dose. Updated PFS will be presented

Background: Efficacy of treatment options for patients with relapsed or refractory classical Hodgkin lymphoma (cHL) is limited. Preclinical and early clinical evidence suggests that blocking the JAK-STAT or PI3K pathways may be efficacious in cHL, both directly and through modulation of the tumor microenvironment. Furthermore, blocking both pathways may provide synergistic efficacy. Aims: To determine the safety, efficacy, and pharmacodynamics of INCB040093 alone or in combination with INCB039110 in patients with relapsed or refractory cHL. Methods: Adult patients with relapsed or refractory B-cell malignancies, including patients with cHL, were enrolled in this ongoing, open-label, dose escalation study. Patients received INCB040093 monotherapy (100 mg once daily, 100 mg twice daily, 150 mg twice daily, or 300 mg once daily) or INCB040093 in combination with INCB039110 (INCB040093: 150 mg daily, 100 mg twice daily, or 150 mg twice daily; INCB039110: 400 mg or 600 mg once daily). Safety, efficacy, and pharmacodynamics were evaluated. Results from patients with relapsed or refractory cHL are reported herein. Results: A total of 17 patients with relapsed or refractory cHL have been enrolled. At baseline, the median age was 34 years and 59% of patients were men. The median number of prior treatment regimens was 5, 82% of patients had undergone prior hematopoietic stem cell transplantation, and all patients had received brentuximab vedotin therapy prior to study entry. The median exposure to treatment in this study was 209 days (range: 22+ [ongoing]-388). The most common nonhematologic adverse events (all grades) in patients with cHL were fatigue (41%), headache(35%), and decreased appetite(35%). Pneumonia( 12%) was the only nonhematologic grade >3 adverse event to occur in >1 patient. All-grade neutropenia, thrombocytopenia, and anemia occurred in 47%, 47%, and 41% of patients, respectively. Grade >3 thrombocytopenia occurred in 18% of patients. No patients with cHL experienced a dose-limiting toxicity. Of 6 evaluable patients receiving INCB040093 monotherapy, the objective response rate (ORR) was 50% (including 1 complete response [CR]); of 9 evaluable patients receiving INCB040093 + INCB039110, ORR was 67% (including 2 CRs). In this limited dataset of proximate dose cohorts, a dose response in efficacy was not evident. INCB040093 100 mg twice daily and INCB040093 100 mg twice daily + INCB039110 400 mg once daily were selected for expansion based on pharmacodynamics and the safety profile of higher dose levels in the overall study population. At the selected doses, ORR in the cHL cohort was 50% for INCB040093 monotherapy and 75% (including 1 CR) for INCB040093 + INCB039110. Summary and Conclusions: INCB040093+/-INCB039110 was generally well tolerated in this heavily pretreated population of patients with relapsed or refractory cHL. Although the number of evaluable patients is limited, efficacy compares well to approved therapies and investigational agents for cHL. This activity warranted further investigation of INCB040093 alone and in combination with INCB039110 in patients with relapsed or refractory cHL, and a phase 2 study has been initiated

Background: Inhibition of the PI3K and JAK-STAT pathways may be efficacious in B-cell malignancies because of their contribution to tumor growth and survival both directly and through modulation of the tumor microenvironment. Furthermore, inhibiting both pathways may result in synergistic efficacy due to JAK-STAT augmentation of B-cell receptor activation of the NFkappaB pathway. Aims: To determine the safety, efficacy, and pharmacodynamics of INCB040093 alone or in combination with INCB039110 in patients with relapsed or refractory B-cell malignancies. Methods: Adults with relapsed/refractory B-cell malignancies were eligible for this ongoing dose escalation study with expansion cohorts. Patients received INCB040093 monotherapy (100 mg once daily, 100 mg twice daily, 150 mg twice daily, or 300 mg once daily) or INCB040093 in combination with INCB039110 (INCB040093: 150 mg daily, 100 mg twice daily, or 150 mg twice daily; INCB039110: 400 mg or 600 mg once daily). Safety, efficacy, and pharmacodynamics were evaluated. Results: A total of 83 patients have been enrolled, including patients with follicular lymphoma (n=19), classical Hodgkin lymphoma (cHL; n=17), diffuse large B-cell lymphoma (DLBCL; n=15), chronic lymphocytic leukemia/small lymphocytic lymphoma (n=13), and other subtypes (n=19). At baseline, the median age was 61 years and 70% of patients were men. The median number of prior regimens received was 4 and 24% of patients had undergone prior hematopoietic stem cell transplantation. The median exposure during the study was 185 days (range: 5-491+ [ongoing]) for INCB040093 alone and 99 days (range: 6-337+ [ongoing]) for INCB040093 + INCB039110. The most common adverse events were fatigue(28%), headache(19%), and pyrexia(19%) and the most common grade >3 adverse event was pneumonia(6%). The most common laboratory abnormalities were liver enzyme elevations and cytopenias. One patient had a dose-limiting toxicity of gastrointestinal bleed secondary to gastric DLBCL regression on INCB040093 100 mg twice daily. INCB040093 100 mg twice daily and INCB040093 100 mg twice daily + INCB039110 400 mg once daily were selected as the dosing regimens for expansion cohorts based on the incidence of liver enzyme elevations with INCB040093 and cytopenias with INCB040093 + INCB039110 at higher doses. At the selected doses, pAKT was decreased by =90% at trough on INCB040093 and IL-6- induced pSTAT3 was decreased an average of 65% on INCB039110. Of 75 evaluable patients, 28 responses have been reported. In evaluable patients with cHL (n=15), the objective response rate was 60%, which included 3 complete responses. Both patients enrolled with the non-germinal center B-cell- like subtype of DLBCL experienced complete responses. Summary and Conclusions: Treatment with INCB040093 alone or in combination with INCB039110 was tolerable and resulted in partial and complete responses in this heavily pretreated population of patients with relapsed or refractory B-cell malignancies. Based on these results, the study was expanded to enroll additional cohorts of patients with relapsed/refractory B-cell malignancies such as DLBCL and cHL, and a phase 2 study was initiated in patients with relapsed/refractory cHL

Although Hodgkin lymphoma (HL) is largely curable with first-line therapy, approximately one-third of patients will not have a complete response to frontline treatment or will subsequently relapse. Only 50 % of these patients will be effectively salvaged with conventional therapies. The prognosis is particularly poor for those patients with chemotherapy refractory disease, who are unable to obtain even transient disease control, and for patients who relapse following high dose chemotherapy and autologous stem cell transplant. In this review, we summarize the most recent updates on the management of patients with relapsed HL, the role of novel therapies such as brentuximab vedotin, and an overview of promising new agents currently under investigation. We also discuss the role of consolidation strategies such as high-dose chemotherapy and autologous stem cell transplant, and reduced-intensity allogeneic hematopoietic stem cell transplant, and the need for new strategies in the elderly patient population.

Although most patients with Hodgkin lymphoma (HL) are cured with primary therapy, patients with primary refractory disease or relapse after initial treatment have poor outcomes and represent an unmet medical need. Recent advances in unraveling the biology of HL have yielded a plethora of novel targeted therapies. This review provides an overview of the data behind the hype generated by these advances and addresses the question of whether or not clinically these targeted therapies offer hope for patients with HL.