Oday Hamid

Multicenter phase II trial of enzastaurin in patients with relapsed or refractory advanced cutaneous T-cell lymphoma

This multicenter, single-arm, open-label non-randomized phase II trial (NCT00744991) was conducted in patients with recurrent/refractory mycosis fungoides (MF), stage IB–IVB, or Sézary syndrome (SS). A Simon two-stage design required 25 patients enrolled in stage 1 with ≥7 confirmed objective responses for expansion into stage 2. Patients were treated with oral enzastaurin (250 mg twice daily) until disease progression or intolerable toxicity. The primary endpoint was investigator-assessed response rate; secondary endpoints were time to objective response, response duration, time-to-progression, patient-reported pruritus, and safety/tolerability. Twenty-five patients were enrolled. A partial response was observed in one patient with MF. Median time-to-progression was 78 and 44 days in MF and SS, respectively. Self-reported pruritus relief and improved composite pruritus-specific symptom scores were documented in six and four patients, respectively. Enzastaurin was well tolerated with mostly grade 1–2 adverse events, mainly diarrhea and fatigue. There were two adverse event-related drug discontinuations with one possibly treatment-related.

Open-label, single-arm, phase II study of enzastaurin in patients with follicular lymphoma.

This open‐label, phase II study investigated whether enzastaurin, a protein kinase C‐beta (PKCβ) inhibitor, had activity in patients with grade 1 or 2 follicular lymphoma (FL). Adults with grade 1 or 2 FL who had no more than one prior treatment received oral enzastaurin continuously for up to 3 years. Of the 66 patients who received enzastaurin, 53 were evaluable for response. Overall response rate (ORR, primary efficacy endpoint) was 26·4% (3·8% complete response). Median (95% confidence interval) progression‐free survival, time to response, and duration of response were 18·1 (11·5–28·3), 4·9 (2·8–8·1), and 22·3 (8·8‐not applicable) months, respectively. In patients with tumour tissue available for biomarker analysis, ORRs in low versus high PKCβ2 expression groups were 41·7% and 8·3%, respectively (P = 0·041). The most common, mainly low‐grade drug‐related adverse events were fatigue (25·8%), diarrhoea (25·8%), nausea (18·2%), and chromaturia (18·2%). Four (6·1%) patients had Grade 3 toxicity and one (1·5%) patient had Grade 4 toxicity. Enzastaurin demonstrated limited clinical activity in grade 1 or 2 FL. Patients with low PKCβ2 expression in tumours had higher ORR than those with high PKCβ2 expression. Enzastaurin was well tolerated with mostly grade 1 or 2 toxicities. Further studies may be warranted in select patient populations.

Dose escalation and pharmacokinetics study of enzastaurin and sunitinib versus placebo and sunitinib in patients with metastatic renal cell carcinoma.

ObjectiveTo assess antiangiogenic effects of enzastaurin in combination with sunitinib in patients with renal cell carcinoma (RCC). MethodsThis was a multicenter, phase 2 study of enzastaurin and sunitinib versus placebo and sunitinib for adult patients with metastatic clear cell RCC. Part 1 was a 6-week, open-label, safety lead-in phase with 2 cohorts (sunitinib, both cohorts: 50 mg/d for 4 weeks; enzastaurin, cohort 1: a loading dose of 500 mg, followed by 250 mg daily; cohort 2: a loading dose of 1125 mg, followed by 500 mg daily). Part 2 was to be a randomized, double-blinded phase, with efficacy as the primary objective. Secondary objectives included the assessment of treatment-emergent adverse events (TEAEs) and pharmacokinetics. ResultsSeventeen patients received ≥1 dose of study medication. Six patients (54.5%) in cohort 1 and 2 patients (33.3%) in cohort 2 received ≥6 cycles of treatment. All patients experienced ≥1 TEAE possibly related to study drug. Dose reductions were required as follows: cohort 1—enzastaurin, n=4 (36.4%), sunitinib, n=6 (54.5%); cohort 2—enzastaurin, n=3 (50.0%), sunitinib, n=2 (33.3%). ConclusionsWhereas the hypothesis that combining sunitinib and enzastaurin may result in greater antiangiogenic effects in RCC is based on solid scientific evidence, part 2 of the study was not activated due to the high number of TEAE-related dose reductions at the expected efficacious dose and overall decision by the sponsor not to pursue further development of enzastaurin for solid tumors.

A randomized phase II study of LY2510924 and carboplatin/etoposide versus carboplatin/etoposide in extensive‐disease small cell lung cancer

OBJECTIVES This multicenter, open-label, randomized phase II study evaluated the efficacy and safety of LY2510924 (LY) added to first-line standard of care (SOC) chemotherapy for extensive-disease small cell lung cancer (ED-SCLC) and explored the predictive value of C-X-C motif receptor 4 (CXCR4) tumor response. MATERIALS AND METHODS Patients with treatment-naïve ED-SCLC were randomized (1:1) to receive up to six 21-day cycles of carboplatin/etoposide alone (SOC) or in combination with 20mg LY2510924 administered subcutaneously on days 1-7 of each cycle (LY+SOC). The primary efficacy endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), overall response rate (ORR), and safety. Response relative to CXCR4 expression on baseline tumor was an exploratory endpoint. RESULTS Of 94 patients randomized, 90 received treatment (LY+SOC, n=47; SOC, n=43). Median PFS (95% confidence interval [CI]) was 5.88 (4.83, 6.24) months for LY+SOC versus 5.85 (4.63, 5.51) months for SOC (hazard ratio [95% CI], 1.01 [0.62, 1.63]; p=0.9806). Median OS (95% CI) was 9.72 (6.64, 11.70) months for LY+SOC versus 11.14 (8.25, 13.44) months for SOC. ORR was 74.5% for LY+SOC versus 81% for SOC. Safety results between arms were similar, although the following adverse events were more frequent on the LY+SOC arm: anemia (61.7% vs 46.5%), neutropenia (61.7% vs 53.5%), leukopenia (27.7% vs 9.3%), vomiting (27.7% vs 16.3%), and pneumonia (10.6% vs 2.3%). In patients whose baseline CXCR4 expression was above the optimal cutoff (H-score 210), the hazard ratio (95% CI) was 1.27 (0.51, 3.15). CONCLUSION LY2510924 did not improve efficacy but had an acceptable toxicity profile when added to SOC for ED-SCLC.

1472PPHASE II STUDY OF CARBOPLATIN/ETOPOSIDE PLUS LY2510924, A CXCR4 PEPTIDE ANTAGONIST, VERSUS CARBOPLATIN/ETOPOSIDE IN PATIENTS WITH EXTENSIVE-STAGE SMALL CELL LUNG CANCER (SCLC)

ABSTRACT Aim: LY2510924, an antagonist to the chemokine receptor CXCR4, inhibits tumor growth and metastasis in xenograft models. A Phase I trial with LY2510924 demonstrated an acceptable safety profile with a robust pharmacodynamic profile. This open-label phase II trial evaluated the clinical benefit of carboplatin/etoposide plus LY2510924 versus carboplatin/etoposide, the standard of care (SOC), as a first-line therapy in patients (pts) with extensive-stage SCLC. Methods: Treatment-naive extensive-stage SCLC pts were randomized 1:1 to receive six 21-day cycles of either LY+SOC (Arm A) or SOC (Arm B). A 20-mg dose of LY2510924 was self-administered by the patient subcutaneously on days 1-7 of each cycle. Efficacy was evaluated using RECIST v. 1.1; adverse events were evaluated using MedDRA v. 14.0. The primary end point, progression-free survival (PFS), was analyzed using a stratified log-rank test. Secondary end points were objective response rate (ORR), duration of overall response (DoR), overall survival (OS), and safety. Results: Median follow-up time was 8.4 months. Pt characteristics were comparable in Arm A (N=47) and Arm B (N=43). Median PFS for Arm A was 5.88 months (95% confidence interval 4.83, 6.24) and Arm B 5.85 months (4.63, 6.51), p=0.9806. ORRs were 74.5% and 81.0%; median DoR were 4.83 months (3.58, 5.09) and 4.67 months (3.32, 5.78) for Arms A and B, respectively. The median OS was 9.72 months (6.64, 11.70) and 11.14 months (8.25, 13.44), p=0.1120 for Arms A and B, respectively. Grade 3/4 treatment-emergent adverse events>8% in Arm A included neutrophil count decrease (40% vs. 56%), anemia (30% vs. 33%), platelet count decrease (23% vs. 16%), lung infection (11% vs. 0%), white blood cell count decrease (9% vs. 9%), and febrile neutropenia (9% vs. 2%) (Arm A vs. Arm B). No pts died due to adverse events. Conclusions: No improvements in PFS, ORR, DoR, or OS in treatment-naive extensive-stage SCLC pts were observed when LY2510924 was added to SOC. The addition of LY2510924 to SOC appeared to increase incidence of lung infection and febrile neutropenia; otherwise, the overall toxicity profile was acceptable in this patient population. Disclosure: O. Hamid: Oday Hamid is employed by Eli Lilly, the sponsor of the study and owns stock in the company; J.R. Stille: Employee of Eli Lilly and Company; J. Polzer: Employee of Eli Lilly and Company. S. Roberson: Employee of Eli Lilly and Company. All other authors have declared no conflicts of interest.

Abstract CT058: Phase I study of LY2874455, a fibroblast growth factor (FGF) receptor inhibitor, in patients with advanced cancer

Background: The fibroblast growth factor (FGF) and FGF receptor pathway has been implicated in several cancers. Inhibition of this pathway has led to the attenuation of tumor growth in preclinical models1. This phase I, first in human dose (FIH) study evaluated safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of LY2874455, an oral FGF receptor inhibitor. Methods: This study had 2 open-label parts. Part A: standard 3+3 patient dose escalation study, identified 16 mg BID as the recommended dose2. Part B: dose expansion study, evaluated 16 mg BID dose in patients (pts) with pretreated advanced gastric cancer (GC) or non-small cell lung carcinoma (NSCLC), who also had ECOG performance status 0-2 and adequate organ function. Treatment continued until disease progression or intolerability. We report here results from Part B of the study. Results: Overall 27 pts in the NSCLC cohort and 31 pts in the GC cohort were treated. Median age was 58.5 years: majority of pts were Asian (89.7%). Pts had received a median of 4 previous lines of chemotherapy. FGFR1 amplification status in the NSCLC group: 29.6% were negative, 7.4% were positive, and status was unknown in 63.0%. For GC pts: 80.6% negative for FGFR2 amplification, 6.5% positive, and status unknown in 12.9%. Both cohorts each received a median of 2 cycles. All 58 pts experienced at least 1 treatment emergent adverse event (TEAE) possibly related to study drug, with 39 pts (67.2%) experiencing at least 1 Grade 3 or 4 TEAE possibly related to study drug. The most common drug-related AEs included: hyperphosphatemia (79.3%), diarrhea (77.6%), anorexia (72.4%), and fatigue (51.7%). Eighteen pts (31.0%) experienced at least 1 serious adverse event (SAE), and 9 pts had SAE possibly related to study drug related. SAEs possibly related to study drug were: fatigue (n = 4), anorexia (n = 3), heamoptysis, central serous retinopathy, keratoconjunctivitis sicca, diarrhea, and hyponatremia. Eleven pts discontinued due to AE or SAE. In the GC cohort, 1 patient, who was FGFR2 amplification negative, had a partial response, and 6 FGFR2 negative pts had stable disease (SD), with 1 patient on treatment for 9 cycles. None of the NSCLC pts responded, but 4 pts had SD (FGFR1 positive n = 2; FGFR1 negative n = 2). Conclusion: Treatment with LY2874455 had a manageable toxicity profile, and preliminary findings suggest anti-tumor activity in gastric cancer. 1. Hattori Y, Itoh H, Uchino S, Hosokawa K, Ochiai A, Ino Y, et al. Immunohistochemical detection of K-sam protein in stomach cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 1996;2:1373-81. 2. Tie, J., et al. “A phase I trial of LY2874455, a fibroblast growth factor receptor inhibitor, in patients with advanced cancer.” Proceedings of the 105th annual meeting of the American Association for Cancer Research 2014;74(19 Suppl):Abstract nr CT215. Citation Format: Jeanne Tie, Yung-Jue Bang, Young Suk Park, Yoon-Koo Kang, David Monteith, Kimberly Hartsock, Oday Hamid, Donald E. Thornton, Michael Michael. Phase I study of LY2874455, a fibroblast growth factor (FGF) receptor inhibitor, in patients with advanced cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT058.

Abstract 5303: Correlative results from PRELUDE, a phase III study of enzastaurin (ENZA) vs placebo (PBO) in patients (pts) with high-risk diffuse large B-cell lymphoma (DLBCL) following a response to R-CHOP therapy

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: Protein kinase Cβ (PKCβ) is critical for B-cell signaling and survival and overexpression of PKCβ in DLBCL is associated with inferior survival. ENZA, an oral serine/threonine kinase inhibitor, targets PKCβ. Here we report immunohistochemical (IHC) and fluorescence in-situ hybridization (FISH) correlative analyses. Methods: PRELUDE ([NCT00332202][1]) was a phase III, double-blind maintenance study of 758 pts with DLBCL who were randomized 2:1 to ENZA 500 mg daily (1125-mg loading dose) (n = 504) or PBO (n = 254), respectively, following CR to induction therapy with R-CHOP. The primary endpoint was disease-free survival (DFS). Overall survival (OS) and assessment of biomarkers specific to ENZA and DLBCL were secondary endpoints. Pre-treatment formalin-fixed, paraffin-embedded samples were assessed via IHC staining in a blinded manner (Eric Hsi) for cell of origin (COO) using Hans’ algorithm. In addition, IHC was performed for c-MYC, BCL2, BCL6, FOXP1, and MUM1 (10% increments/% tumor cells stained), markers relevant to ENZA, including PKCβ2. FISH was performed to identify translocations involving c-MYC, BCL2, and BCL6. Cox regression was used to determine statistical associations between efficacy outcomes and dichotomized markers, adjusting for treatment and additional baseline covariates. All tests of association were conducted at a 2-sided α = 0.05. Results: There was no difference in 4-year DFS (70% vs 71%) or OS (81% vs 82%) between ENZA and PBO arms, respectively. A total of 243 (32%) pts had ≥1 evaluable sample available for IHC and FISH. There was no difference in outcome for pts based on COO (GCB vs non-GCB). Independent of treatment, significant associations were observed for BCL2 (pre-specified cutpoint 20%) and MUM1 (cutpoint 30%) with OS, and FOXP1 (cutpoint 80%) by IHC with DFS (HR [95% CI]: 2.19 [1.01-4.73]), p = 0.031; 1.97 [1.04-3.71], p = 0.032; 1.74 [1.04-2.90], p = 0.032, respectively). Associations were not significant for other IHC markers, including c-MYC and BCL6. Low PKCβ2 (<50% expression) had numerically better (but not significant) DFS/OS vs high PKCβ2. Dual translocation lymphoma by FISH was identified in two pts (1.2%) each for c-MYC/BCL2 and c-MYC/BCL6, and one pt (0.6%) had a triple hit involving c-MYC/BCL2/BCL6. Conclusions: No difference in outcomes between treatment arms was observed for the trial. Independent of treatment, COO was not prognostic of outcomes. Pts with low PKCβ2 expression had numerically better DFS/OS compared with high PKCβ2 expression. Significant treatment-independent associations were observed for BCL2 and MUM1 with OS and for FOXP1 with DFS (low IHC expression corresponded to better outcomes). The small number of double hit and triple hit lymphomas seen in the study may reflect the enrollment of CR patients with more favorable biology. Citation Format: Eric D. Hsi, Kerry J. Savage, Sonali M. Smith, Fritz Offner, Scott P. Myrand, Thomas M. Habermann, Donald E. Thornton, Boris K. Lin, Tuan S. Nguyen, Oday Hamid, Michael Crump. Correlative results from PRELUDE, a phase III study of enzastaurin (ENZA) vs placebo (PBO) in patients (pts) with high-risk diffuse large B-cell lymphoma (DLBCL) following a response to R-CHOP therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5303. doi:10.1158/1538-7445.AM2015-5303 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00332202&atom=%2Fcanres%2F75%2F15_Supplement%2F5303.atom