Selinexor is a novel, first-in-class, selective inhibitor of nuclear export compound, which blocks exportin 1 (XPO1) function, leads to nuclear accumulation of tumor suppressor proteins, and induces cancer cell death. A phase 1 dose-escalation study was initiated to examine the safety and efficacy of selinexor in patients with advanced hematological malignancies. Ninety-five patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled between January 2013 and June 2014 to receive 4, 8, or 10 doses of selinexor in a 21- or 28-day cycle. The most frequently reported adverse events (AEs) in patients with AML were grade 1 or 2 constitutional and gastrointestinal toxicities, which were generally manageable with supportive care. The only nonhematological grade 3/4 AE, occurring in >5% of the patient population, was fatigue (14%). There were no reported dose-limiting toxicities or evidence of cumulative toxicity. The recommended phase 2 dose was established at 60 mg (∼35 mg/m) given twice weekly in a 4-week cycle based on the totality of safety and efficacy data. Overall, 14% of the 81 evaluable patients achieved an objective response (OR) and 31% percent showed ≥50% decrease in bone marrow blasts from baseline. Patients achieving an OR had a significant improvement in median progression-free survival (PFS) (5.1 vs 1.3 months; = .008; hazard ratio [HR], 3.1) and overall survival (9.7 vs 2.7 months; = .01; HR, 3.1) compared with nonresponders. These findings suggest that selinexor is safe as a monotherapy in patients with relapsed or refractory AML and have informed subsequent phase 2 clinical development. This trial was registered at www.clinicaltrials.gov as #NCT01607892.
Background: Concerns have been raised whether immune checkpoint inhibitor therapy in the alloBMT setting will result in graft versus host disease (GvHD) and transplant related mortality (TRM). We report our experience with a variety of checkpoint inhibitors used before or after allogeneic bone marrow transplantation (alloBMT). Our series comprises patients who received T cell-replete hematopoietic stem cells from HLA-haploidentical or -matched donors and is limited to those treated with post-transplant cyclophosphamide (PTCy) as primary GvHD prophylaxis. Patient selection: We retrospectively reviewed the records of alloBMT recipients who received PTCy and received checkpoint inhibitor therapy before or after alloBMT. GvHD was assessed using the CIBMTR GVHD index. Results: Eleven patients received checkpoint inhibitor therapy prior to alloBMT: anti-PD-1: Nivolumab n=6, anti-CTLA4: Ipilimumab n=8 (3 patients received both nivolumab and ipilimumab). These patients received a median of 4 (range 1 - 18) cycles of therapy. The median interval from last checkpoint inhibitor treatment to day of transplant was 43 (range 18-302) days. All patients received nonmyeloablative conditioning; 6 received partially mismatched allografts (5 were HLA haploidentical). Four patients developed Grade II aGvHD: Three patients who had received partially mismatched allografts (haplo-2, 9/10 unrelated-1) experienced stage 3 cutaneous GvHD only; one patient who received a 10/10 unrelated donor allograft developed stage 3 cutaneous GvHD with stage 1 liver involvement. Three patients were on immunosuppression when GvHD developed, the fourth patient with cutaneous and liver GvHD had been taken off tacrolimus on day 68 due to concerns of graft failure. GvHD resolved with treatment in each case. None of these patients developed chronic GvHD and none have died [median follow-up of 0.66 (range 0.91 - 2.0) years post alloBMT]. Nine patients received checkpoint therapy following alloBMT: anti-PD-1: Pembrolizumab n = 1, Nivolumab n= 6, anti-CTLA4: Ipilimumab n= 3 (one patient received nivolumab and ipilimumab). Eight patients had received nonmyeloablative conditioning; 5 received haploidentical allografts. Six received treatment for relapse of their hematologic malignancy, 1 for relapsed pediatric sarcoma, and 2 for newly diagnosed lung cancer. The median time to initiation of checkpoint inhibitor therapy was 1.2 (range: 0.8 - 5.8) years post alloBMT. Patients received a median of 5 (range 1 - 24) cycles of therapy. There was 1 case of Grade II aGvHD; stage 3 cutaneous GvHD when DLI from a 10/10 matched unrelated donor was given for relapsed disease after ipilimumab. This resulted in GvHD which was not accompanied by the desired graft-vs-leukemia effect. There were no other cases of acute or chronic GvHD in this group. There were 4 tumor-related deaths: pediatric sarcoma (1), lung cancer (1), and AML (2). The median follow-up for this group is 2 years (range 0.85 - 8.0) post alloBMT. Conclusions: In this small series, the incidence and severity of GvHD seen in patients who received checkpoint inhibitors was similar to that seen in patients treated with PTCy as GvHD prophylaxis without checkpoint inhibitors. GvHD was seen in patients treated with checkpoint inhibitors prior to alloBMT, but was generally mild and readily controlled and there were no associated deaths. In patients treated with checkpoint inhibitors after alloBMT, the only case of GvHD occurred after the patient received DLI. We caution that use of checkpoint inhibitors in closer temporal proximity to transplant might well be associated with increased risk of GvHD or severity of GvHD. Disclosures Borrello: WindMIL Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding. Wagner-Johnston:Seattle Genetics: Research Funding. Smith:Celgene: Consultancy, Other: member of DSMB.
NCT01492088) and adult studies (NCT00412282) were performed to quantify sources of variability, including body size effects, on ADC and monomethyl auristatin E (MMAE) PK in paediatric pts with classical Hodgkin lymphoma (cHL). Methods: POPPK base-models were based on previously reported models. A full model was developed including all statistically-relevant prespecified covariate effects; a final model was chosen by retaining only the significant covariate effects (p<0.001). Model parameters were estimated using NONMEM (v7.3). The final model was used to simulate mg/kg or body surface area (BSA)-based dosing scenarios in paediatric pts to inform selection of posology that provides exposures matching those achieved in adults with weight-based (mg/kg) dosing.Results: Data were collected from 84 pts with a median age of 25.7 years (range 7-87, 34 of whom [40.5%] were aged <18 years), median weight of 67 kg (range 21-154), and median BSA of 1.8 m 2 (range 0.86-2.8). ADC PK was described by a linear 3-compartment model with zero-order input and first-order elimination. In covariate analyses, BSA was the best predictor of body size effects on ADC PK, and was a strong predictor of clearance (CL), V 1 , and V 3 ; anti-drug 526 ABSTRACT remarkable response to single-agent therapy with ALRN-6924, a stapled dual MDM4/MDM2-inhibiting peptide, suggests particularly impressive efficacy of this novel targeted therapy for MDM4-amplified cases, and implies clinically detectable cytogenetic MDM4 amplifications as a possible biomarker to guide future use and patient selection.ABSTRACT 527
Introduction DLBCL is the most common lymphoid neoplasm in adults (Swerdlow 2016). While durable CRs are achieved in approximately 70% of patients (pts) with frontline RCHOP therapy (Pfreundschuh 2008), pts with high-risk features often experience disease resistance or relapse. In Part 1 of an ongoing study, pts with high-intermediate or high risk DLBCL by international prognostic index (IPI) scores, regardless of CD30 expression by IHC, were treated with 1.2 or 1.8 mg/kg brentuximab vedotin (BV) combined with RCHOP. After 3 of the first 10 pts treated at 1.8 mg/kg BV+RCHOP developed Grade 3 peripheral neuropathy (per Standardized MedDRA Query [SMQ]), all pts enrolled subsequently received treatment with 1.2 mg/kg BV+RCHOP. Following completion of enrollment in Part 1, the protocol was amended to enroll a non-randomized portion of the study (Part 2) evaluating the safety and efficacy of 1.8 mg/kg BV+RCHP (Yasenchak 2015), followed by an open-label, randomized portion comparing BV+RCHP to RCHOP (Part 3). Initial results from Part 2 and updated results from Part 1 are reported here. Methods For Part 2 of the study, pts with CD30-expressing high-intermediate and high-risk DLBCL were treated with up to 6 cycles of 1.8 mg/kg BV+RCHP (NCT01925612). Key inclusion criteria were CD30 expression by IHC performed by a local pathology lab and standard IPI scores of 3-5 or age-adjusted IPI (aaIPI) scores of 2-3 (high-intermediate/high risk). CD30 expression was confirmed by a central pathology lab, although CD30 expression by local pathology lab was required for eligibility. Disease response was evaluated with PET/CT per Cheson 2007. Results At the time of analysis for this ongoing study, 11 pts in Part 2 were treated with BV+RCHP (7 male, 4 female; 22-78 yrs). Of these pts, 9 had high-intermediate risk (IPI 3, aaIPI 2) and 2 had high risk disease (IPI 4-5, aaIPI 3), 6 had Stage IV disease, and 6 had an ECOG score of 2. At the end of treatment, the overall response rate was 91% (9 CR, 1 PR); 1 pt had PD after Cycle 4. The most frequent (>20%) treatment-emergent adverse events (AEs) were alopecia and nausea (73% each); fatigue (64%); constipation and peripheral sensory neuropathy (55% each); neutropenia and throat irritation (36% each); and chills, diarrhea, headache, and stomatitis (27% each). Grade 3 or 4 AEs occurred in 8 pts and 5 pts had serious AEs, which included febrile neutropenia, bacteremia, nausea, pneumocystis jiroveci pneumonia, pulmonary embolism, and vomiting. Peripheral sensory neuropathy occurred in 6 pts and all were Grade 1 or 2 events; no peripheral motor neuropathy AEs were reported. No AEs were fatal or led to discontinuation. One pt discontinued treatment after Cycle 4 due to disease progression. For the first 51 pts in Part 1, the progression-free survival (PFS) at 18 months for pts with CD30 expression (25 pts) or without detectable CD30 expression (24 pts) by IHC was 79% (95% CI: 57%, 91%) versus 58% (95% CI: 36%, 75%), respectively. Overall survival for pts was 92% (95% CI: 71%, 98%) versus 71% (95% CI: 48%, 85%), respectively. Ten pts had pre-existing peripheral neuropathy (per SMQ) at study entry. Treatment-emergent peripheral neuropathy (per SMQ) was observed in 75% of pts (38/51) who received BV+RCHOP; 55% of these pts (21/38) had resolution of all or some peripheral neuropathy events. Conclusions 1.8 mg/kg BV+RCHP is active as frontline treatment in CD30-expressing, high-intermediate/high risk DLBCL. When combined with RCHP, 1.8 mg/kg BV appears to be well-tolerated. The PFS and OS for pts with CD30-expression who received BV+RCHOP appear promising. The study is currently ongoing in pts with CD30-expressing high-intermediate/high risk DLBCL to assess the safety and activity of 1.8 mg/kg BV+RCHP versus standard RCHOP. Disclosures Halwani: Bristol Myers-Squibb: Research Funding; Kyowa Hakko Kirin: Research Funding; Takeda: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Other: Travel Expenses, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; Miragen: Research Funding; Pharmacyclics: Consultancy; Amgen: Research Funding. Yasenchak:Seattle Genetics: Research Funding. Farber:Seattle Genetics: Research Funding. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Fayad:Seattle Genetics: Consultancy, Research Funding. Holkova:Seattle Genetics: Research Funding. Knapp:Insys Therapeutics, Inc.: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Kolibaba:Gilead: Consultancy, Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; janssen: Research Funding; GSK: Research Funding; Genentech: Research Funding; Acerta: Research Funding. Patel-Donnelly:Seattle Genetics: Research Funding. Yimer:Ariad Pharmaceuticals: Consultancy; Biotheranostics: Consultancy; Bluebird Bio: Equity Ownership; Kite Pharma: Equity Ownership; Clovis Oncology: Equity Ownership; Juno Therpeutics: Equity Ownership; Seattle Genetics: Research Funding. Smith:Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Research Funding. Levy:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau; Seattle Genetics: Research Funding; Actinium Pharmaceuticals, Inc.: Research Funding. Seetharam:Seattle Genetics: Research Funding. Belada:Seattle Genetics: Research Funding. Brooks:Seattle Genetics: Research Funding. Kingsley:Gilead: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Wagner-Johnston:Seattle Genetics: Research Funding. Ruffner:Forma Therapeutics: Consultancy; Sydnax: Consultancy; Seattle Genetics: Employment, Equity Ownership; Array Biopharma: Employment; Medivation: Employment. Bartlett:Gilead: Consultancy.
Atypical response patterns following immune checkpoint blockade (ICB) in Hodgkin lymphoma (HL) led to the concept of continuation of treatment beyond progression (TBP); however, the longitudinal benefit of this approach is unclear. We therefore performed a retrospective analysis of 64 patients treated with ICB; 20 who received TBP (TBP cohort) and 44 who stopped ICB at initial progression (non‐TBP cohort). The TBP cohort received ICB for a median of 4.7 months after initial progression and delayed subsequent treatment by a median of 6.6 months. Despite receiving more prior lines of therapy, the TBP cohort achieved longer progression‐free survival with post‐ICB treatment (median, 17.5 months vs. 6.1 months, p = .035) and longer time‐to‐subsequent treatment failure, defined as time from initial ICB progression to failure of subsequent treatment (median, 34.6 months vs. 9.9 months, p = .003). With the limitations of a retrospective study, these results support the clinical benefit of TBP with ICB for selected patients.
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