Preliminary Evidence Of Antitumor Activity Research Articles

Phase I dose escalation study of BI 836826 (CD37 antibody) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma

SummaryBI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a tetraspanin transmembrane protein predominantly expressed on normal and malignant B cells. This phase I, open-label study used a modified 3 + 3 design to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary activity of BI 836826 in patients with relapsed/refractory B cell non-Hodgkin lymphoma (NHL; NCT01403948). Eligible patients received up to three courses comprising an intravenous infusion (starting dose: 1 mg) once weekly for 4 weeks followed by an observation period of 27 (Course 1, 2) or 55 days (Course 3). Patients had to demonstrate clinical benefit before commencing treatment beyond course 2. Forty-eight patients were treated. In the dose escalation phase (1–200 mg) involving 37 Caucasian patients, the MTD was 100 mg. Dose-limiting toxicities occurred in four patients during the MTD evaluation period, and included stomatitis, febrile neutropenia, hypocalcemia, hypokalemia, and hypophosphatemia. The most common adverse events were neutropenia (57%), leukopenia (57%), and thrombocytopenia (41%), and were commonly of grade 3 or 4. Overall, 18 (38%) patients experienced infusion-related reactions, which were mostly grade 1 or 2. Preliminary evidence of anti-tumor activity was seen; three patients responded to treatment, including one complete remission in a Korean patient with diffuse large B cell lymphoma. BI 836826 plasma exposure increased more than proportionally with increasing doses. BI 836826 demonstrated preliminary activity; the most frequent adverse events were hematotoxicity and infusion-related reactions which were manageable after amending the infusion schedule. Although BI 856826 will not undergo further clinical development, these results confirm CD37 as a valid therapeutic target in B cell NHL.

Final Results of Phase 1, Dose Escalation Study Evaluating ARQ 531 in Patients with Relapsed or Refractory B-Cell Lymphoid Malignancies

Final Results of Phase 1, Dose Escalation Study Evaluating ARQ 531 in Patients with Relapsed or Refractory B-Cell Lymphoid Malignancies

1189PD - Determinants of response of HER2+ gastric cancer (GC) vs gastroesophageal junction adenocarcinoma (GEJ) to margetuximab (M) plus pembrolizumab (P) post trastuzumab (T)

1189PD - Determinants of response of HER2+ gastric cancer (GC) vs gastroesophageal junction adenocarcinoma (GEJ) to margetuximab (M) plus pembrolizumab (P) post trastuzumab (T)

461P - First in human phase I/IIa study of PEN-866, a heat shock protein 90 (HSP90) ligand – SN38 conjugate for patients with advanced solid tumours: Phase I results

461P - First in human phase I/IIa study of PEN-866, a heat shock protein 90 (HSP90) ligand – SN38 conjugate for patients with advanced solid tumours: Phase I results

Abstract CT022: A Phase Ib study of Wee1 inhibitor adavosertib in patients with advanced solid tumors

Abstract Background: Adavosertib is a highly selective inhibitor of Wee1, a crucial regulator of intra-S and G2/M cell cycle checkpoints. This Phase Ib study (NCT02610075) investigated dosing and schedule for adavosertib monotherapy and determined the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients (pts) with advanced solid tumors. Methods: Pts received adavosertib orally once (QD) or twice daily (BID) on a 5/9 schedule (5 days on treatment followed by 9 days off) in 14-day cycles, or one of two 5/2 dosing schedules (5 days on followed by 2 days off; weekly or 2 out of 3 weeks) in 21-day cycles. MTD was determined using a 3+3 dose-escalation cohort design. DLTs were defined as toxicities related to adavosertib, occurring during the first cycle. PK and biomarker analyses were performed on blood samples. Pts’ response to treatment was assessed using RECIST v1.1. Results: 62 pts (female, 64.5%; median age, 61.5 years; most common primary tumor sites: lung [24.2%] and ovary [21.0%]) received treatment (QD schedule, n=50; BID schedule, n=12) (Table 1). Median treatment duration was 1.77 months. Adavosertib was steadily absorbed (median time to max concentration: 2.0-4.15 h) and slowly eliminated (mean half-life: 5-12 h). AEs leading to dose reductions, interruptions and discontinuations were reported by 17 (27.4%), 25 (40.3%) and 4 (6.5%) pts, respectively. The most common grade ≥3 AEs were anemia, neutropenia (both n=9, 14.5%) and diarrhea (n=8, 12.9%). The overall response rate was 3.4% (n=2 [thymoma; anal]), disease control rate 48.4% (n=30) and median progression-free survival 2.7 months. Circulating-tumor-derived DNA pharmacodynamic analyses will be presented. Conclusions: The MTD was determined to be 125 mg (BID 5/9) and 300 mg (QD 5/2 and 5/9) for 2/3 weeks, with 300 mg (QD 5/2) being the RP2D. The safety/tolerability profile was considered acceptable. Adavosertib monotherapy showed preliminary evidence of antitumor activity in a heavily pretreated patient population. Table 1CohortAdavosertib dose (schedule)N evaluableAny AE Grade ≥3, n (%)DLTs, n (%)DLTs:* AE preferred term/CTCAE gradeBID 1125 mg (5/9)64 (66.7)0–BID 2150 mg (5/9)65 (83.3)2 (33.3)Diarrhea/3 and nausea/2 Dehydration/3QD 1.1200 mg (5/9)51 (20.0)0–QD 1.2200 mg (5/2)53 (50.0)0–QD 2.1250 mg (5/9)42 (50.0)0–QD 2.2250 mg (5/2)33 (100.0)0–QD 2.3250 mg (5/2 weekly)95 (50.0)2 (22.2)Thrombocytopenia/3 and neutropenia/3 Thrombocytopenia/2QD 3.1300 mg (5/9)43 (75.0)0–QD 3.2300 mg (5/2)1512 (75.0)2 (13.3)Nausea/2 and weight decreased/1 Pneumonia/3QD 3.3300 mg (5/2 weekly)21 (50.0)2 (100.0)Thrombocytopenia/4 Nausea/2 and vomiting/2Total5939 (62.9)8125/2: doses given on days 1–5 and 8–12 per 21-day cycle; 5/2 weekly schedule: doses given on days 1–5, 8–12 and 15–19 per 21-day cycle; 5/9: doses given on days 1–5 per 14-day cycle. *Some patients experienced >1 DLT. CTCAE, Common Terminology Criteria for Adverse Events; DLT, dose-limiting toxicity Citation Format: Gerald S. Falchook, Jasgit Sachdev, Esteban Rodrigo Imedio, Sanjeev Kumar, Ganesh Mugundu, Juliann Chmielecki, Suzanne Jones, David R. Spigel, Melissa Johnson. A Phase Ib study of Wee1 inhibitor adavosertib in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT022.

Clinical activity of ipilimumab plus nivolumab (Ipi/Nivo) in patients (pts) with metastatic non-clear cell renal cell carcinoma (nccRCC).

e16084 Background: Ipi/Nivo is a standard of care for pts with metastatic clear cell RCC. The clinical activity of Ipi/Nivo in patients with metastatic nccRCC remains poorly defined. Methods: Metastatic nccRCC pts who were treated with Ipi/Nivo at Cleveland Clinic or UT Southwestern were retrospectively reviewed. Ipi/Nivo was administered as per CHECKMATE 214. Computed tomography imaging was obtained at baseline and every 12 weeks to assess disease response per RECIST 1.1 criteria. Baseline pt characteristics, outcome to therapy and adverse effects as per CTCAE v5.0 were collected. Results: Eighteen pts with metastatic nccRCC histology who were treated with Ipi/Nivo were identified. The median age was 60 years (range, 32-81). Non clear cell histologies included adenocarcinoma of renal origin not otherwise specified (2), unclassified (3), papillary (6), chromophobe (5), translocation (1) and medullary histology (1). ECOG PS was 0 (7 pts); 1 (9 pts) and 2 (2 pts). Fourteen patients were male and four female. IMDC risk group at the time of initiation of Ipi/Nivo was favorable (2 pts), intermediate (14 pts) and poor (2 pt). Fourteen pts received Ipi/ Nivo as first line treatment, two pts received Ipi/Nivo after prior TKI and two pts received Ipi/ Nivo as third line treatment after prior chemotherapy and nivolumab monotherapy. In total, fourteen pts had restaging scans with four pts demonstrating partial response (PR 28%), two with stable disease (SD 14%) and eight with progressive disease (PD 58%). Four pts died (22%) – three from the disease and one from treatment related complication (encephalitis).Four pts experienced diarrhea- three pts (grade 2) and one pt ( grade 3) , three developed hepatotoxicity- one pt (grade 2) and two pts (grade 3), one pt each developed hypophysitis (grade 3), fatigue (grade 2) , rash (grade 2) and encephalitis (grade 3). All 100% pts required steroids, one each got infliximab and Mycophenolate Mofetil. . All 100% pts required steroids, one each got infliximab and Mycophenolate Mofetil. Conclusions: Ipi/Nivo is feasible and safe in patients with metastatic nccRCC with preliminary evidence of anti-tumor activity

Phase 1 study of AMG 119, a chimeric antigen receptor (CAR) T cell therapy targeting DLL3, in patients with relapsed/refractory small cell lung cancer (SCLC).

TPS8576 Background: SCLC is an aggressive neuroendocrine tumor, with initial sensitivity to chemotherapy and radiotherapy often followed by chemoresistant disease progression. Notch signaling is a key regulator of neuroendocrine differentiation in SCLC, and delta-like ligand 3 (DLL3) is an inhibitory ligand of Notch receptors. DLL3 is expressed in most SCLC tumors but minimally expressed in normal tissues, suggesting that it may be a promising target for cancer immunotherapy. AMG 119 is an adoptive cellular therapy that consists of a patient’s autologous T cells that have been genetically modified ex vivo to express a transmembrane CAR that targets DLL3 and redirects cytotoxic T cell specificity to DLL3-positive cells. AMG 119 CAR T cells show potent killing of SCLC cells expressing DLL3 in vitro and inhibit tumor growth in an SCLC xenograft model in vivo. Methods: This phase 1 study will evaluate the safety and tolerability of AMG 119 administered as a single infusion in adult patients with relapsed/refractory SCLC who have progressed after at least 1 platinum-based chemotherapy regimen. The primary objectives are to evaluate safety and tolerability and determine the maximum tolerated cell dose (MTCD) or recommended phase 2 cell dose (RP2CD). Secondary objectives are to evaluate preliminary evidence of antitumor activity, expansion and persistence of AMG 119, and trafficking of AMG 119 to the tumor in post-treatment biopsy. Key inclusion criteria include histologically confirmed SCLC with radiographically documented disease progression or recurrence after at least 1 platinum-based regimen, ECOG performance status 0–1, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. In the cell dose exploration phase, 3–4 patients will receive a single IV infusion of AMG 119 at each cell dose. Cell dose escalation/de-escalation decisions will be guided by a modified toxicity probability interval design. The dose expansion phase will seek to confirm the MTCD or RP2CD and obtain further safety and efficacy data. Clinical trial information: NCT03392064.

Open-label, multicenter, phase I study to assess safety and tolerability of adavosertib plus durvalumab in patients with advanced solid tumors.

2562 Background: Adavosertib (AZD1775; A) is a highly selective inhibitor of WEE1. This Phase I study (NCT02617277) investigated a range of doses and schedules for oral A plus IV durvalumab (DV), a human monoclonal antibody targeting PD-L1, to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients (pts) with advanced solid tumors. Methods: Four 28-day schedules (Sch) were evaluated with pts receiving DV 1500 mg on day (d) 1 of each schedule (Table). Patients continued treatment if they showed clinical benefit in the absence of any discontinuation criteria. Pts received A monotherapy for PK analysis prior to the start of combination therapy in Sch B, C (d –7 to –5) and D (d –9 to –5). MTD was determined using a 3+3 dose-escalation cohort design. Predefined dose-limiting toxicities (DLTs) were evaluated during the first cycle of study treatment. Results: 54 pts received A (most common primary tumor sites: colon, 19%; lung, 13%; breast, 11%). The most common grade ≥3 AEs were fatigue (15%), diarrhea (11%) and nausea (9%). DLTs were nausea (n = 2) and diarrhea (n = 1). 7 pts (13%) had A-related SAEs, including reversible and confounded drug-induced liver injury (Sch B 125 mg and Sch C; 1 each). Disease control rate (DCR) for the total cohort was 36%. Preliminary PK at 150 mg BID suggests adequate coverage for cell kill activity and no drug–drug interaction. Conclusions: The MTD/RP2D was A 150 mg BID (3 d on, 4 d off; treatment d 15–17, 22–24) with DV 1500 mg (d 1 Q4W); safety profile was considered acceptable. Preliminary evidence of antitumor activity was observed. Clinical trial information: NCT02617277. [Table: see text]

Phase I trial of IACS-010759 (IACS), a potent, selective inhibitor of complex I of the mitochondrial electron transport chain, in patients (pts) with advanced solid tumors.

3014 Background: A subset of tumors possess genetic or microenvironmental alterations that render cells dependent on mitochondria oxidative phosphorylation (OXPHOS) for survival. IACS, a potent oral selective inhibitor of mitochondrial complex I, showed robust responses in multiple preclinical tumor models, providing strong rationale for clinical testing. Methods: Pts with advanced cancers received IACS in increasing dose levels (DL) using 3+3 dose escalation. 7-day QD induction of IACS was followed by maintenance weekly (QW) or twice weekly (BIW) dosing. Phamacokinetics (PK), lactate and pH were assessed serially. Paired tumor biopsies were assessed for pharmacodynamic and predictive biomarkers. Results: 18 pts were treated; M/F 16/2; ECOG PS 0/1: 3/15. Mean age 49 (23-69) yrs. Tumors comprised advanced colorectal (n = 4), castration resistant prostate cancer (CRPC) (n = 3), pancreatic (n = 2), other cancers (n = 9). DL1: 2mg QD 7 days induction/0.5mg QW maintenance (n = 3); DL2: 2.5mg QD 7 days/1mg QW (n = 3); DL3: 3mg QD 7 days/3mg QW (n = 3); DL4: 2.5mg QD 7 days/2.5mg BIW (n = 4); DL5: 2mg QD 7 days/2mg BIW (n = 5). IACS was well tolerated with 12 (67%) pts reporting G1-2 IACS related toxicities, such as raised lactate (n = 10), nausea (n = 8), fatigue (n = 7), vomiting (n = 5), myalgia (n = 4) and peripheral neuropathy (n = 4). 1 pt in DL3 and 2 pts in DL4 had ≥G3 IACS related toxicities, such as nausea (n = 2), vomiting (n = 1), raised lactate (n = 1), dehydration (n = 1), visual changes (n = 1), and peripheral neuropathy (n = 1). Raised lactate was not associated with acidosis. DL5 is now being expanded to assess the maximum tolerated dose (MTD). PK showed good oral bioavailability, with long T1/2 and low intrapatient variability. Cmax = 14nM on Day 7 at the end of DL5 induction phase, confirming biologically active doses. 7 pts had best response of RECIST stable disease. A pt with heavily pretreated CRPC achieved RECIST partial response with resolution of CRPC related pain. Conclusions: IACS is well tolerated with preliminary evidence of antitumor activity. MTD expansions include CRPC, TNBC, pancreatic cancer and molecularly selected (ENO1 loss; SMARCA4 mutation) tumor cohorts. Clinical trial information: NCT03291938.

Clinical activity of ipilimumab plus nivolumab (Ipi/Nivo) in patients (pts) with metastatic non-clear cell renal cell carcinoma (nccRCC).

659 Background: Ipi/Nivo is a standard of care for pts with metastatic clear cell RCC. The clinical activity of Ipi/Nivo in patients with metastatic nccRCC remains poorly defined. Methods: Metastatic nccRCC pts who were treated with Ipi/Nivo at Cleveland Clinic or UT Southwestern were retrospectively reviewed. Ipi/Nivo was administered as per CHECKMATE 214. Computed tomography imaging was obtained at baseline and every12 weeks to assess disease response per RECIST 1.1 criteria. Baseline pt characteristics, outcome to therapy and adverse effects as per CTCAE v5.0 were collected. Results: Thirteen pts with metastatic nccRCC histology who were treated with Ipi/Nivo were identified. The median age was 60 years (range, 32-81). Non clear cell histologies included adenocarcinoma of renal origin not otherwise specified (2), unclassified (3), papillary (3), chromophobe (3), translocation (1) and medullary histology (1). Nine pts had ECOG PS 0; four pts had ECOG PS 1. Eleven patients were male and two female. IMDC risk group at time of initiation of Ipi/Nivo was favorable (2 pt), intermediate (10 pts) and poor (1 pt). Nine pts received Ipi/ Nivo as first line treatment, three pts received Ipi/Nivo after prior TKI and one pt received Ipi/ Nivo as third line treatment after prior chemotherapy and nivolumab monotherapy. In total, eight pts have thus far undergone restaging scans with three pts demonstrating partial response (PR), one pt demonstrating stable disease (SD) and four pts demonstrating progressive disease (PD). Two pts experienced grade 2 diarrhea, one after 4 cycles and another after 3 cycles of Ipi/Nivo and required prednisone. One pt demonstrated grade 3 hepatotoxicity after 2 cycles of Ipi/Nivo and required prednisone and Mycophenolate Mofetil while another pt demonstrated grade 1 hepatotoxicity after 3 cycles of Ipi/ Nivo requiring prednisone. One pt experienced grade 2 pancreatitis requiring steroids after one dose of Ipi/Nivo. One pt experienced grade 2 fatigue after 1 cycle of Ipi/Nivo requiring prednisone. Conclusions: Ipi/Nivo is feasible and safe in patients with metastatic nccRCC with preliminary evidence of anti-tumor activity. Updated clinical data will be presented.

Ipilimumab plus nivolumab (Ipi/Nivo) as salvage therapy in patients with immunotherapy (IO)-refractory metastatic renal cell carcinoma (mRCC).

669 Background: Ipi/Nivo is now FDA approved for the first line treatment of patients (pts) with intermediate and poor risk mRCC but activity in IO refractory mRCC patients is still not well reported. Here we seek to report activity of Ipi/Nivo in IO refractory mRCC pts. Methods: In this retrospective review, we identified a total of 30 pts with mRCC from 4 academic medical centers across the USA who received salvage Ipi/Nivo after disease progression on IO therapy. Pts with only predominant clear cell histology were captured. Ipi/Nivo was administered as per CHECKMATE 214. Investigator-assessed response rate were noted. Immune related adverse events (irAE) were captured in accordance with CTCAE v5.0. Results: The baseline demographics included median age of 60 years (21-82), ECOG PS 0-2, and 73% (22) male and 27% (8) female. IMDC risk categories at the time of salvage Ipi/Nivo initiation were 23% (7), 60% (18) and 3% (1) with favorable, intermediate and poor risk, respectively. The median number of prior systemic therapies was 3 (1-6). Prior IO therapies included nivolumab monotherapy (14), avelumab plus axitinib (3), high dose interleukin-2 (3), pembrolizumab monotherapy (2) and Ipi/Nivo, nivolumab plus hypoxia inducible factor (HIF) inhibitor, atezolizumab plus interferon, atezolizumab monotherapy, pembrolizumab plus bevacizumab, pembrolizumab plus axitinib, varlilumab plus atezolizumab and an oral adenosine inhibitor (1 each). The median time on prior IO therapy was 7 months (1-50), best response was 3% (1) CR, 40% (12) PR, 23% (7) SD and 33% (10) PD. 73% (22) had restaging scans to assess response to ipi/nivo of which 17% (5), 3% (3) and 47% (14) showed PR, SD and, PD respectively. 37% (11) developed any grade irAEs and 6% (2) had grade ≥3 irAE including one patient with splenic rupture and one with rash and pneumonitis. Conclusions: Ipi/Nivo is feasible and safe in IO-refractory mRCC population with preliminary evidence of anti-tumor activity. Updated response data will be presented.

A Phase 1 Dose Escalation Study of ARQ 531 in Selected Patients with Relapsed or Refractory Hematologic Malignancies

Background: Aberrant activation of B-cell receptor (BCR) signaling is considered to be a major oncogenic mechanism that leads to the development and progression of multiple B-cell malignancies. ARQ 531 is a reversible ATP competitive inhibitor of BTK that inhibits ibrutinib-resistant BTK-C481S mutant CLL cells and has demonstrated antitumor activity in CLL, Richter's transformation, and DLBCL mouse models.Objectives: The primary objectives of the clinical study are to assess the safety and tolerability, and to determine the recommended Phase 2 dose and schedule of ARQ 531. The secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of anti-tumor activity of ARQ 531.Methods: This is a first in human, Phase 1 dose escalation study in patients with relapsed or refractory CLL/SLL, Waldenstrom's macroglobulinemia, or B-cell NHL who received at least 2 prior lines of systemic therapy. Prior therapy must have included a BTK inhibitor, if FDA approved for their disease. Dose escalation was performed according to a 3+3 study design. Treatment emergent adverse events (TEAEs) were assessed per NCI CTCAE v.4.03. Tumor responses were evaluated per disease specific guidelines.Results: A total of 16 patients enrolled (median age 65.5 years, male 93.8%, 2 DLBCL, 2 follicular lymphoma, 12 CLL/SLL, 5 median prior systemic regimens) and were treated at dose levels of 5, 10, 15, 20 and 30mg QD. No dose limiting toxicities have been reported with ARQ 531. Drug related TEAEs included diarrhea, nausea, vomiting, fatigue, pneumonia, amylase increased, lipase increased, neutrophil count decreased, platelet count decreased, decreased appetite, hypernatraemia, arthralgia, groin pain, dizziness, facial paralysis, headache, tremor and restlessness in one patient (6.3%) each. Drug related grade 3 or worse TEAEs included lipase increased and platelet count decreased in one patient (6.3%) each. No drug related serious TEAEs were reported. Among the 12 patients who have received at least 1 dose of study drug and have at least 1 post-treatment tumor measurement data, 5 achieved stable disease (SD) (1 follicular lymphoma, 1 DLBCL, 3 CLL) and 7 had progressive disease (6 CLL, 1 follicular lymphoma). Three of 5 SD patients (1 follicular lymphoma, 1 DLBCL, 1 CLL) had 35%, 34% and 29% tumor reduction and 2 of them are ongoing on study treatment at 53 and 18 weeks. The CLL patient with 29% tumor reduction had BTK C481S mutation.Preliminary PK data showed ARQ 531 exposure was close to dose proportional and the estimated plasma half-life generally ranged from 20-24 hours. Consistent with increases in exposure, pBTK knockdown was observed. In Cohort 4 (20mg QD), all three patients showed 100% pBTK knockdown at a mean plasma Cmax exposure of 300nM (~4h post dose). Levels of CCL3 protein, a plasma biomarker for BCR pathway activation, was significantly suppressed in CLL patients.Conclusions: ARQ 531 has demonstrated a manageable safety profile to date. Diminished pBTK signaling and CCL3 protein levels have been observed in CLL patients. Additionally, preliminary anti-tumor activity has been observed at doses of ARQ 531 that were not predicted to completely inhibit BTK. Updated safety, PK, biomarker and anti-tumor activity data will be presented at the meeting. DisclosuresFlinn:Gilead: Research Funding; Infinity: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Kite: Research Funding; Verastem: Consultancy, Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; Curis: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Janssen: Research Funding; ArQule: Research Funding; Calithera: Research Funding; Genentech: Research Funding; Forma: Research Funding; Agios: Research Funding; Constellation: Research Funding; Trillium: Research Funding; Verastem: Research Funding; Portola: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Forty Seven: Research Funding; BeiGene: Research Funding. Savage:ArQule, Inc.: Employment. Eathiraj:ArQule, Inc.: Employment. Tith:ArQule, Inc.: Employment.

1832PD - Phase I study of CC-90011 in patients with advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma (R/R NHL)

Background: CC-90011 is a selective, reversible inhibitor of the epigenetic target, lysine-specific demethylase 1A (LSD1) that has demonstrated anti-tumor activity against neuroendocrine cells in vitro and in xenograft models. Methods: This is a phase I, first-in-human clinical study of CC-90011 in patients (pts) with advanced unresectable solid tumors and R/R NHL. Pts received oral CC-90011 once/week in 28-day cycles. Primary objectives were to determine safety, maximum-tolerated dose (MTD), and/or recommended phase II dose (RP2D). Secondary objectives were to measure preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD). Results: As of 15 Jan 2018, 35 pts were enrolled; 34 with advanced solid tumors, including 17 with neuroendocrine tumors (NETs) and 1 with R/R NHL. They received escalating doses of CC-90011 at 1.25 mg (n = 4), 2.5 mg (n = 5), 5 mg (n = 6), 10 mg (n = 4), 20 mg (n = 4), 40 mg (n = 6), or 80 mg (n = 4). The MTD and RP2D have not yet been established. The median age was 61 y (range, 22-75), 19 (54%) were male, with 2 (range, 1-4) median number of prior systemic anticancer therapies. No dose-limiting toxicities were reported. The only treatment-related grade 3/4 adverse event (AE) was thrombocytopenia (9%). Serious AEs occurred in 24% of pts; none were treatment-related. Peak plasma concentrations were 2-4 hours post-dose and terminal elimination half-life was approximately 64 hours; increase in plasma exposures was dose proportional. Blood biomarker analyses showed increasing suppression of MMD and MYL9 expression with higher CC-90011 doses suggesting target engagement at doses ≥ 40 mg. Overall, 13 (39%) pts had stable disease (SD). Prolonged SD (≥4 mo) was observed in 5 pts with solid tumors; notably, 3 of those pts had bronchial NETs [5 mg (n = 1), 20 mg (n = 1) and 40 mg (n = 1)]. Preliminary PD results from NETs showed CC-90011 decreased chromogranin A levels, correlating with clinical benefit. Conclusions: CC-90011 has dose-proportional PK with target engagement at tolerable doses with preliminary evidence of antitumor activity in advanced solid tumors and R/R NHL, including prolonged SD particularly in pts with NETs. Clinical trial identification: NCT02875223. Editorial acknowledgement: Editorial assistance was provided by BioConnections, LLC. Legal entity responsible for the study: Celgene Corporation. Funding: Celgene Corporation. Disclosure: A. Hollebecque: Honoraria: Merck Serono; Consulting or advisory role: Gritstone Oncology; Travel, accommodations: Amgen. J. de Bono: Consulting or advisory role: AstraZeneca, GlaxoSmithKline, Genentech, Pfizer, Merck, Sharp & Dhome, Bayer, Merck Serone, Janssen, Astellas, Seattle Genetics; Research funding: AstraZeneca, Sanofi, Genentech, GlaxoSmithKline, Daiichi, Taiho, Merck Serone, Merck Sharp & Dhome, Sierra; Speaker's bureau: AstraZeneca. R. Plummer: Honoraria: Novartis, Bristol-Myers Squibb, AstraZeneca; Consulting or advisory role: Clovis Oncology, Bayer, Novartis, Pierre Faber, Karus Therapeutics, Genmab, Octimet; Research funding: Merck, Genmab, AstraZeneca, Menarini; Patents, royalties, other intellectual property: Clovis Oncology; Travel, accommodations: Merck Sharpe & Dhome, Bristol-Myers Squibb. S. Mora, A. Harding, Z. Nikolova: Employment, equity ownership, travel, accommodations: Celgene, Inc. A. Nguyen: Employment, equity ownership, patents, royalties, other intellectual property: Celgene Corporation. E. Filvaroff: Employment: Celgene; Equity ownership: Celgene, Amgen, Gilead, Genentech, Roche; Patents, royalties, other intellectual property: Celgene, Genentech. M. Lamba: Employment, equity ownership, research funding: Pfizer Inc., Celgene Corporation; Patents, royalties, other intellectual property: Pfizer, Inc. K. Liu, M. Zuraek: Employment, equity ownership: Celgene Corporation. J. DiMartino: Employment, leadership, equity ownership: Celgene Corporation. All other authors have declared no conflicts of interest.

Safety and tolerability of quizartinib, a FLT3 inhibitor, in advanced solid tumors: a phase 1 dose-escalation trial

BackgroundQuizartinib, an inhibitor of class III receptor tyrosine kinases (RTKs), is currently in phase 3 development for the treatment of acute myeloid leukemia (AML) bearing internal tandem duplications in the FLT3 gene. Aberrant RTK signaling is implicated in the pathogenesis of a variety of solid tumors, suggesting that inhibiting quizartinib-sensitive RTKs may be beneficial in precision cancer therapy.MethodsThis was a phase 1, open-label, modified Fibonacci dose-escalation study of orally administered quizartinib in patients with advanced solid tumors whose disease progressed despite standard therapy or for which there was no available standard treatment. Patients received quizartinib dihydrochloride (henceforth referred to as quizartinib) once daily throughout a 28-day treatment cycle. The primary endpoint was evaluation of the maximum tolerated dose (MTD) of quizartinib. Secondary endpoints included preliminary evidence of antitumor activity and determination of the pharmacokinetic and pharmacodynamic parameters of quizartinib.ResultsThirteen patients were enrolled. Five patients received a starting dose of quizartinib 135 mg/day; dose-limiting toxicities (DLTs) of grade 3 pancytopenia, asymptomatic grade 3 QTc prolongation, and febrile neutropenia were observed in 1 patient each at this dose. A lower dose of quizartinib (90 mg/day [n = 8]) was administered without DLTs. The most common treatment-related treatment-emergent adverse events (AEs) were fatigue (n = 7, 54%), dysgeusia (n = 5, 38%), neutropenia (n = 3, 23%), and QTc prolongation (n = 3, 23%). Overall, all patients experienced at least 1 AE, and 4 experienced serious AEs (2 patients each in the 135-mg and 90-mg dose groups) including hematologic AEs, infections, and gastrointestinal disorders. Six patients (including 3 patients with gastrointestinal stromal tumors [GIST]) had a best response of stable disease.ConclusionThe MTD of quizartinib in patients with advanced solid tumors was 90 mg/day. Overall, the safety and tolerability of quizartinib were manageable, with no unexpected AEs. Quizartinib monotherapy had limited evidence of activity in this small group of patients with advanced solid tumors.Trial registrationClinical Trials Registration Number: NCT01049893; First Posted: January 15, 2010.

Phase 1 dose-escalation study of ACT001 in patients with recurrent glioblastoma and other advanced solid tumors.

e14048 Background: ACT001 is an orally-available parthenolide derivative which inhibits NF-κB signaling, has immunomodulatory effects and showed promising activity in preclinical models of glioblastoma (GBM). We performed a first-in-human clinical trial of ACT001 in patients with advanced solid tumors, including GBM. Methods: Eligible patients were ≥ 18 yrs and ECOG PS 0-1, with satisfactory hematologic, renal and hepatic function. GBM patients additionally had progressive disease (PD) despite initial radiation and temozolomide, measurable tumor, no radiation in the prior 3 months and no previous treatment with anti-VEGF drugs. ACT001 was given orally BID until intolerance or PD, and dose escalation followed a standard 3+3 design. Gliomas were imaged with MRI every 8 weeks and responses assessed using RANO criteria. Results: A total of 13 patients were enrolled: 10 with GBM, 2 with anaplastic glioma and 1 with pleural mesothelioma. Median age was 53 yrs (range, 34-72). ACT001 dose levels were 100 mg BID, 200 mg BID, 400 mg BID and 600 mg BID. Study treatment was well tolerated and no dose-limiting toxicities have occurred. Of 12 evaluable patients, best responses were a partial response in 1 GBM patient (ongoing after 10+ months of treatment), stable disease in 3 patients and PD in 8 patients. ACT001 plasma half life was 3-4 hours and no accumulation was observed after multiple dosing. At ≥ 400 mg BID, drug concentrations expected to have biological activity were reached. Conclusions: At well-tolerated doses, ACT001 showed satisfactory bioavailability and preliminary evidence of anti-tumor activity in a subset of patients. Clinical trial information: ACTRN12616000228482.

TRITON3: An international, randomized, open-label, phase III study of the PARP inhibitor rucaparib vs. physician’s choice of therapy for patients with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination deficiency (HRD).

TPS389 Background: Recent data have shown that up to 25% of patients with advanced prostate cancer, including mCRPC, have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM, or another homologous recombination DNA repair gene. Such mutations can be used as a molecular marker to select patients for targeted treatment with poly(ADP-ribose) polymerase inhibitors (PARPis), which are lethal to cells with HRD. Treatment with PARPis has shown preliminary evidence of antitumor activity in patients with mCRPC and a mutation in a homologous recombination DNA repair gene (Mateo et al. N Engl J Med. 2015;373:1697-708). These data provide a compelling rationale for evaluating rucaparib, a potent inhibitor of PARP1, PARP2, and PARP3, in patients with mCRPC associated with HRD. Methods: TRITON3 (NCT02975934) is a randomized, phase 3 study evaluating rucaparib 600 mg BID vs physician’s choice of abiraterone, enzalutamide, or docetaxel in patients with mCRPC and a deleterious germline or somatic BRCA1, BRCA2, or ATM mutation (identified by prior local testing or central testing during screening). Patients must have progressed on androgen receptor signaling–directed therapy in the mCRPC setting; prior PARPi treatment or chemotherapy for mCRPC are exclusion criteria. Patients will be randomly assigned in a 2:1 ratio to either rucaparib or physician’s choice, with the possibility for cross over from the comparator treatment to rucaparib upon radiographic progression confirmed by independent radiology review. The primary endpoint is radiographic progression-free survival (modified RECIST v1.1/PCWG3 criteria) assessed by independent radiology review. Secondary endpoints include objective response rate, duration of response, patient-reported outcomes, overall survival, and safety. Pretreatment blood samples collected from all patients will enable development of a noninvasive plasma-based companion diagnostic to select patients who may benefit from rucaparib treatment. Patients (≈400) will be enrolled at > 100 sites worldwide. Clinical trial information: NCT02975934.

RX‐3117, an oral hypomethylating agent to treat advanced solid tumors: Interim results from an ongoing phase 2a study in advanced urothelial cancer (aUC).

501 Background: RX-3117 is an oral small molecule hypomethylating agent, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 shows efficacy in various xenograft models, including those of gemcitabine resistant bladder cancer. Preliminary data from Stage 2 of a Phase 2a clinical study of RX‐3117 as a single agent in subjects with aUC is described below. Methods: This Phase 2a study (2‐stage design, NCT02030067) evaluates the efficacy of RX‐3117 in eligible patients (aged ≥ 18 years) with refractory aUC. Primary objectives include safety and efficacy of the recommended Phase 2 dose and schedule identified in the Phase 1 portion of the study. Patients received 700 mg of oral RX‐3117 daily for either 3 weeks with 1 week off in each 4-week cycle or 4 continuous weeks. The primary endpoint is a ≥ 20% rate of progression free survival benefit (i.e., proportion of patients with stable disease for at least 4 months) and/or a 10% of evaluable patients with a partial response or better. Results: As of October 2017, 17 patients (12 males, 5 females) with aUC were treated with RX‐3117. The median age was 66 years, ECOG performance status was 0 to 1 and 53% received ≥ 3 prior therapies. Metastatic disease sites included lung, liver, lymph nodes, and mediastinum. Four patients achieved stable disease for 4 cycles of RX‐3117 treatment; one patient received treatment for 168 days and another patient for 301 days. One patient showed tumor shrinkage as measured by RECIST (‐15.5%) after 4 cycles of RX-3117; another patient showed a 19% tumor reduction after 1 cycle. The most frequent related adverse events were G1 diarrhea (13%), fatigue (13%), nausea (10%), G1/G2 anemia (10%), vomiting (10%) and G3 thrombocytopenia (10%). Conclusions: RX‐3117 is safe and well tolerable and shows preliminary evidence of anti-tumor activity. The study continues to enroll patients with aUC in Stage 2. Clinical trial information: NCT02030067.

Abstract P5-21-04: Phase I/Ib study of the SERD LSZ102 alone or in combination with ribociclib in ER+ breast cancer

Abstract Background: LSZ102 is an orally bioavailable selective estrogen receptor degrader (SERD) that inhibits estrogen receptor (ER) gene transcription, induces receptor degradation, and blocks ER-dependent cell growth in preclinical models. This Phase I/Ib, open-label study is evaluating LSZ102 as a single agent and in combination with the CDK4/6 inhibitor ribociclib (LEE011) or the PI3K inhibitor alpelisib (BYL719) in patients (pts) with locally advanced/metastatic ER-positive (ER+) breast cancer (BC). Methods: The primary objective is to characterize the safety and tolerability, and identify a recommended dose and regimen of LSZ102 alone (Arm A) or in combination with ribociclib (Arm B) or alpelisib (Arm C). Secondary objectives include evaluation of preliminary antitumor activity and pharmacokinetics (PK). Eligible pts (aged ≥18 yrs; ECOG PS 0-1) have histologically confirmed ER+ BC that has progressed after endocrine therapy. Results: As of March 14, 2017, dose escalation evaluating 16 pts in Arm A (LSZ102 200 mg [n=4], 400 mg [n=6], and 600 mg [n=6]) had completed (median age 57.5 yrs; 81% ECOG PS 0; 63% received prior fulvestrant). Five pts (median age 59.0 yrs; 80% ECOG PS 0; 60% received prior fulvestrant) had enrolled in the first cohort of Arm B (LSZ102 200 mg QD + ribociclib 300 mg 3 weeks on/1 week off) with evaluation ongoing. Arm C (LSZ102 + alpelisib) had yet to open. As of March 14, 2017, 9/16 (56%) pts in Arm A had discontinued treatment, all due to progressive disease (PD); in Arm B all pts were still receiving treatment. There were no dose-limiting toxicities in either arm at the dose levels evaluated; dose escalation is ongoing. The most common drug-related adverse events (AEs) were diarrhea (Grade [Gr] 1: 7/16; Gr 2: 2/16 pts), nausea (Gr 1: 6/16; Gr 2: 2/16 pts), and vomiting (Gr 1: 3/16 pts) in Arm A, and hot flush, nausea, vaginal discharge (all Gr 1: 2/5 pts), thrombocytopenia (Gr 1: 1/5; Gr 2: 1/5 pts), and neutropenia (Gr 2: 1/5, Gr 3: 1/5 pts) in Arm B. There were no drug-related Gr 3/4 AEs reported in Arm A; in Arm B, Gr 3 neutropenia, leukopenia, and lymphopenia each occurred in 1/5 pts. Preliminary PK assessment showed single-agent LSZ102 exposure increased dose-proportionally from 200 to 600 mg QD. In combination with ribociclib, exposures were consistent with those of the single agent at the same dose. In Arm A, preliminary evidence of antitumor activity was observed. Efficacy data for Arms B and C were not available as of March 14, 2017. One pt, whose tumor harbored an ESR1 D538G mutation, had been treated with multiple prior therapies in the metastatic setting, including letrozole, exemestane, tamoxifen, exemestane + everolimus, and anastrozole, as well as fulvestrant for 120 days prior to PD, and letrozole + palbociclib for 94 days prior to PD. As of March 14, 2017, this pt had been on LSZ102 treatment (400 mg QD) for 167 days, with a best response of stable disease (14% reduction in sum of diameter of target lesions). Conclusions: Oral single-agent LSZ102 appears well-tolerated, with a manageable safety profile. Preliminary data also suggest tolerability when combined with ribociclib. Preliminary evidence of single-agent antitumor activity was seen in heavily pretreated pts with ER+ BC in a post-fulvestrant setting. Citation Format: Juric D, Curigliano G, Cresta S, Yap Y-S, Terret C, Duhoux FP, Takahashi S, Kundamal N, Bhansali S, Liao S, Crystal A, Jhaveri K. Phase I/Ib study of the SERD LSZ102 alone or in combination with ribociclib in ER+ breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-04.

Phase I study of E7046, a novel PGE2 receptor type 4 inhibitor, in patients with advanced solid tumors: Clinical results and effects on myeloid- and T-lymphoid cell-mediated immunosuppression.

49 Background: E7046 is a selective inhibitor of the prostaglandin E2 (PGE2) receptor EP4, which transduces potent immunosuppressive activity of PGE2 in myeloid and T-lymphoid cells. In preclinical studies, E7046 reversed PGE2-mediated activities and facilitated activation of cytotoxic T-cells. Here, we present initial clinical, PK and PD results from a first-in-human study of E7046 in patients (pts) with cancers having high myeloid cell infiltration. Methods: E7046 was given orally, once-daily, in 21-day cycles in sequential dose-escalating cohorts (125, 250, 500 and 750mg). Tumor responses were evaluated by irRECIST and metabolic responses by 18FDG-PET. Immune response modulation was assessed in tumors and peripheral blood. Results: Thirty pts were treated, with no dose-limiting toxicities observed. The most common adverse events were fatigue (37%), diarrhea (33%), and nausea (30%). Grade 3/4 AEs in > 1 pt were abdominal pain (3 pts) and vomiting (2 pts). Grade 3/4 treatment-related AEs occurred in 4 pts (rash in 2 pts, and diarrhea, allergic reaction, anaphylaxis, hypersensitivity, and hyperuricemia, in 1 pt each). Four pts discontinued E7046 due to an AE (bowel obstruction, allergic reaction, abdominal pain, acute renal failure). No objective tumor responses were reported. Treatment duration of ≥20 wks with best response of stable disease (SD) was observed in 5 pts, 3 of whom had partial metabolic responses. E7046 exposure was dose-proportional up to 500 mg. Elimination half-life (12 hr) justified once-daily dosing. E7046 treatment significantly increased tumor CD3+ and CD8+ T-cell infiltration, and blood levels of the T-cell-recruiting chemokine CXCL10. E7046 also modulated blood expression of EP4 signaling genes (IDO1, EOMES, PD-L1). Longer duration of therapy with SD was associated with higher baseline tumor infiltrate of CD8+ T-cells and CD163+ macrophages. Conclusions: E7046 demonstrated favorable tolerability with preliminary evidence of anti-tumor activity and immune modulation in tumor and peripheral blood. MTD was not reached. Further studies of E7046 in combination with other agents are planned. Clinical trial information: NCT02540291.

A first-in-human phase I study of sEphB4-HSA (sEphB4) with expansion in hepatocellular (HCC) and cholangiocarcinoma (CCA).

285 Background: EphrinB4, a receptor kinase, is associated with stage and survival in epithelial cancers. sEphB4 is a fusion protein of soluble EphB4 and albumin. sEphB4 binds to EphrinB2, a protein expressed in tumor cells and vessels, and blocks bidirectional signaling. sEphB4 downregulates the PI3K/AKT/mTOR pathway, inhibits angiogenesis, and promotes recruitment of cytotoxic T cells and NK cells. MTD was not reached during dose escalation. The RP2D was 10 mg/Kg weekly. Here we report the results of the expansion cohorts in HCC and CCA. Methods: The study evaluated the safety, PK, PD and efficacy of sEphB4 in pts with advanced solid tumors in a 3+3 design with expansion at the RP2D in 7 solid tumors including HCC and CCA. Pts received sEphB4 10 mg/kg IV weekly in 28-day cycles. Eligibility included ECOG 0-1, Child-Pugh score ≤ 7, platelets > 50,000, AST/ALT ≤ 3xULN, serum bilirubin ≤ 1.5mg/dL and no uncontrolled hypertension. Results: 29 pts were treated: 17 HCC and 12 biliary cancers (8 CCA and 4 gallbladder). Median age was 63(25-77). ECOG PS was 1 in 76%. Median prior regimens were 1 (0-6) for HCC and 2 (1-3) for biliary cancers. 2 HCC pts had prior liver transplantation, 9 had prior anti PD-1 therapy and 2 had Child-Pugh score of B7. Median number of cycles was 4 (1-21) in HCC and 2 (1-17) in CCA. No grade 4 treatment-related adverse events (TRAE). Grade 3 TRAE were hypertension (41%) and fatigue, headache, neutropenia all in 1 pt each. Disease progression was the most common reason for treatment discontinuation. Median PFS in months was 5.0 (3.0-7.5) in HCC and 3.0 (1.6-9.2) in CCA. Median OS in months was 27.1 (4.4-27.1) in HCC and 12.0 (3.0-28.2) in CCA. Disease control rate was 70% in HCC and 42% in CCA including 1 PR in HCC. In HCC pts, 5/5 with 3+ EphrinB2 expression in tumor had PR or SD ≥ 6 months. Only 1/4 pts with ≤2+ expression had SD ≥ 4 months. 3/3 pts with HCC showed an increase in T cell infiltration, and decrease in pS6 (PI3K pathway activity) on post-treatment biopsy. Conclusions: sEphB4 has a manageable safety profile with preliminary evidence of anti-tumor activity in pretreated pts with HCC and biliary cancers. Several trials combining sEphB4-HSA with cytotoxic chemotherapy or immunotherapy are ongoing. Clinical trial information: NCT01642342.