bluuebunny/crossref_metadata_2025 huggingface dataset:
Final results from the dose-escalation stage of a phase 1/2 trial of TPI 287, a brain penetrable microtubule inhibitor, plus bevacizumab in patients with recurrent glioblastoma.
Authors: Goldlust Samuel Aaron , Nabors Louis B. , Mohile Nimish , Benkers Tara L. , Hsu Sigmund H. , Silberman Sandra , Singer Samuel , Rao Mayank , Cappello Lori , Farmer George
Published: September 2018

2021

Background: Microtubule inhibitors, including taxanes, are active in preclinical models of glioblastoma (GBM), however, clinical benefit is hampered by poor blood-brain barrier (BBB) accumulation. TPI 287, a third-generation taxane designed to evade P-glycoprotein mediated efflux, readily penetrates the BBB and overcomes this limitation. CB-017 is a multi-center phase 1/2 trial designed to determine the optimal dose of TPI 287 and potential efficacy in patients treated with this drug plus bevacizumab (BEV) for treatment of recurrent GBM. Final results of the dose escalation Phase 1 stage of this trial are reported. Methods: GBM patients at first or second relapse after standard therapy and without prior exposure to anti-angiogenic agents were eligible for enrollment. BEV was administered at 10 mg/kg every 2 weeks and TPI 287 every 3 weeks via IV infusion. MRIs were obtained every six weeks with response assessed via RANO criteria. TPI 287 dose escalation was based on a traditional 3+3 design. Results: Twenty-four patients were enrolled in 7 TPI 287 dose-escalation cohorts (140-220 mg/m2) from 6 U.S. centers. Twenty and 23 patients were evaluable for response and survival, respectively. Median follow-up was 28 months. Results are shown in the table below. Of the 9 patients from which biomarker data was available, tumors from 8 patients (89%) harbored an unmethylated MGMT promoter, an established negative prognostic indicator for survival. No DLTs were reported and myelosuppression (n=3) was the only drug-related grade 3/4 adverse event. Conclusions: TPI 287 in combination with BEV is safe and well tolerated at doses up to 220 mg/m2. Final survival results from the Phase 1 portion of this study compare favorably with historical controls and support further investigation of TPI 287 plus BEV for treatment of recurrent GBM. Clinical trial information: NCT01933815. [Table: see text]
Phase I/II study of an implantable device delivering low intensity pulsed ultrasound (LIPU) to disrupt the blood-brain barrier (BBB) followed by intravenous carboplatin chemotherapy in patients with recurrent glioblastoma (GBM).
Authors: Idbaih Ahmed , Canney Michael , Vignot Alexandre , Law-Ye Bruno , Dehais Caroline , Houillier Caroline , Laigle-Donadey Florence , Delattre Jean-Yves , Carpentier Alexandre
Published: September 2018

2034

Background: The BBB prevents the passage of most drugs from the blood to the brain and may be responsible for the limited efficacy of current chemotherapies in GBM patients. Two to four minutes of LIPU in combination with injection of micron-sized microbubbles has been shown to be a safe method for disrupting the BBB for a duration of 6 hours to increase the passage of drugs such as carboplatin by 5 to 7 fold in normal brain. Methods: Patients with recurrent GBM were implanted with a 1 MHz, 10-mm diameter pulsed ultrasound device in a burr hole during additional debulking surgery or during a dedicated procedure under local anesthesia. Ultrasound dose was escalated using a 3+3 Simon design. The device was activated monthly in combination with injection of a sulfur hexafluoride microbubble to transiently disrupt the BBB in 5 cm3 of the tumor field before IV administration of carboplatin chemotherapy (AUC4-6). Patients received 150-270 seconds of pulsed ultrasound < 1 hour prior to chemotherapy. BBB disruption was visualized using contrast-enhanced T1w MRI, and patients were monitored clinically and with T2, FLAIR, DWI and SWI sequences. Tumor progression was evaluated using the RANO criteria. Results: Nineteen patients were treated by LIPU until tumor progression. In 65 ultrasound sessions, 52 showed BBB disruption. The median number of monthly sonications per patient was 3 and ranged from 1-10. No significant adverse events related to ultrasound sonications were observed. Six patients (31%) had long PFS (19, 20, 35, 38, 40, 52 weeks). When tumor recurrence occurred, it was predominantly outside of the ultrasound sonication field. Conclusions: This trial has demonstrated that LIPU is a safe modality for disrupting the BBB in GBM patients and may increase the effectiveness of drug therapies in the brain. The sonication of larger volumes of brain may further increase the effectiveness of this therapy in patients with GBM. Clinical trial information: NCT02253212.
Phase I study (BLOOM) of AZD3759, a BBB penetrable EGFR inhibitor, in EGFRm NSCLC patients with leptomeningeal metastasis (LM) who progressed after other anti-cancer therapy.
Authors: Cho Byoung Chul , Ahn Myung-Ju , Lee Jong-Seok , Kim Dong-Wan , Kim Sang-We , John Tom , Kao Stephen Chuan-Hao , Goldman Jonathan Wade , Su Wu-Chou , Natale Ronald B. , Ahn Jin Seok , Kim HyeRyun , Kim Tae Min , Lin Chia-Chi , Overend Philip , Yang Zhenfan , Yang James Chih-Hsin
Published: September 2018

2069

Background: AZD3759 is the first EGFR inhibitor primarily designed to effectively cross the blood brain barrier (BBB) to treat central nervous system (CNS) metastases. A phase I study is ongoing to assess AZD3759 in EGFRm NSCLC patients with leptomeningeal metastasis (LM) who progressed after other treatment (NCT02228369). Methods: The primary objective is safety and tolerability, and secondary objectives include anti-tumor efficacy. Two dose levels of AZD3759, 200 mg and 300 mg BID, were assessed. Results: As of24 September, 2016,38 patients were recruited into the expansion cohorts of this phase I study. Of those, 18 were TKI pre-treated EGFRm NSCLC patients with LM. 10 and 8 patients were in the 300 and 200 mg BID cohorts, respectively. No DLTs were observed at either dose, while AZD3759 was better-tolerated at 200 than 300 mg BID during > 2 month treatment. The longest duration on treatment was > 9 months. Most common AEs included skin rash and diarrhea. 67% (12 out of 18) patients had drug-related dose interruption and/or reduction, however, there were no drug-related discontinuations.The Ctrough free plasma and CSF exposure were above pEGFR IC90at the two doses. 40% of patients (4 out of 10) had > 50% inhibition of pEGFR in CSF tumor cells at C1D8, and 70% of patients (7 out of 10) had reduced EGFR copy numbers in CSF at C3D1. 53% of evaluable patients (9 out of 17) had confirmed improved/stable LM MRI imaging. 2 out of 3 patients with concomitant measurable BM lesions achieved confirmed/unconfirmed partial CNS response. Among 18 patients with measurable extracranial lesions, 6 (33%) had confirmed stable extracranial disease as best response. 3 patients achieved clearance of tumor cells in CSF by two consecutive assessments. After 6 months follow-up, 29% patients (5 out of 17 evaluable) were still surviving, plus 5 surviving patients with less than 6 months follow-up. Conclusions: AZD3759 was well-tolerated, achieved sufficient CNS exposure for target inhibition and demonstrated promising anti-tumor activity in patients with LM who progressed after multiple lines of treatment. Updated clinical data will be shared at the meeting. Clinical trial information: NCT02228369.
Neurocognitive function testing and health related quality of life in stage IV lung cancer patients with and without brain metastases.
Authors: O'Kane Grainne M. , Tse Brandon C , Tam Vivian , Brown M Catherine , Lu Lin , Borean Michael , Tse Tiffany , Labbe Catherine , Naik Hiten , Mittman Nicole , Tam Emily , Doherty Mark , Leighl Natasha B. , Bradbury Penelope Ann , Shepherd Frances A. , Howell Doris , Liu Geoffrey
Published: September 2018

2073

Background: Survival in stage IV lung cancer (S4LC) patients (pts) continues to improve, highlighting the importance of assessing health related quality of life (HRQoL). Lung cancer, involvement with brain metastases (BM), and systemic or brain-specific treatment can all impact neurocognitive function (NCF) and HRQoL. We evaluated the relationship between NCF and HRQoL in S4LC pts by BM status. Methods: S4LC pts with BM (BM+) were frequency distributionally-matched to pts without BM (NBM). NCF was measured using the Hopkins Verbal Learning Test – Revised (HVLT-R), the Controlled Oral Word Association Test (COWAT) and Trail Making Tests (TMT-A/B); scores were correlated with health utility score (HUS) data from EQ5D-3L surveys (Pearson Coefficient, R). Results: BM+ (n = 54) and matched NBM (n = 40) pts had similar demographics. The overall median age was 61years; 59% were female; of 89% that were adenocarcinomas, half had EGFR/ALK alterations; mean time since diagnosis was 2.6 years; mean time since BM were diagnosed in BM+ pts was 0.5 years. Mean HUS (mHUS) were similar between groups: 0.77 for BM+ vs. 0.78 for NBM; p = 0.86. However, pts with stable BM had higher HUS than those with progressive BM (mHUS: 0.80 vs 0.69; p = 0.045). Of BM+ pts, 44% had received whole brain radiation (WBRT). Correlations of NCF and HUS specific for BM+ pts were observed for several HLVT scores, including Total Recall (TR), which was correlated with HUS in BM+ (R = 0.35, p = 0.01) but not in NBM (R = 0.04, p = 0.84) and Recognition Discrimination Index (BM+: R = 0.32, p = 0.03 vs NBM: R = 0.13, p = 0.51). In contrast, TMT-A/B NCF test results had slightly stronger associations with HUS in NBM pts. COWAT was least associated with HUS in BM+ or NBM pts. In BM+ pts treated vs untreated with WBRT, HLVT scores were better in untreated patients (TR, p < 0.0001; delayed recall, p = 0.006; retention, p = 0.089), associations not seen with either TMT-A/B or COWAT. Mutation status had no bearing on these associations. Conclusions: NCF impacts HUS in S4LC pts and should be considered in treatment planning. HVLT scores are useful to assess specifically the impact of BM and WBRT in S4LC pts, and is reflected in associations with HRQoL.
A phase I study of PF-06647263, a novel EFNA4-ADC, in patients with metastatic triple negative breast cancer.
Authors: Garrido-Laguna Ignacio , Krop Ian E , Burris Howard , Hamilton Erika Paige , Braiteh Fadi S. , Weise Amy , Abu-Khalaf Maysa M. , Zopf Christopher , Lakshminarayanan Mani , Holland Jaymes S. , Baffa Raffaele , Hong David S. , Hassan Raffit
Published: September 2018

2511

Background: PF-06647263 is an anti-Ephrin-A4 (EFNA4) antibody drug conjugate (ADC) composed of a humanized mAb, a hydrazone cleavable linker, and calicheamicin, a potent DNA damaging agent. Higher levels of EFNA4 expression have been shown in tumor versus normal tissue, including in two thirds of triple negative breast cancers (TNBC). In vivo preclinical studies demonstrate PF-06647263 induced tumor regression in TNBC models. Methods: In Part 1 of a dose escalation, cohorts of 2-12 patient (pts) with solid tumors that were unselected for EFNA4 expression received escalating doses of PF-06647263 once every 3 weeks (Q3W, Cohort A) or weekly (QW, Cohort B). Escalations were based on mTPI design. An expansion cohort enrolled TNBC patients (n=12) unselected for EFNA4 expression. Efficacy, safety, EFNA4 RNA expression, pharmacokinetic (PK) and anti-drug antibody development were assessed. Results: Part 1 (dose escalation):A total of 48 pts (25 in A and 23 in B) wereenrolled. The most common treatment related adverse events (AE) were fatigue (65%), and nausea (60%), thrombocytopenia (40%), and decreased appetite (38%). DLTs were observed in 6 and 2 pts in the Q3W and QW regimens, respectively. One confirmed VOD and one suspected VOD were observed in two patients in the Q3W schedule. The maximum tolerated dose (and RP2D) was determined to be 0.015 mg/kg QW. Confirmed partial responses (PR) were observed in 5 pts (3 Ovarian Ca and 2 TNBC). Part 2 (TNBC dose expansion at RP2D)data are available on 10 of 12 pts treated (2 ongoing). The most common adverse events (AE) were nausea (40%), asthenia (30%), vomiting (30%) and mucosal inflammation (30%). No objective RECIST response was observed; there was no dependency with duration of treatment relative to EFNA4 expression. Conclusions: In Part 1 of this study, PF-06647263 was generally well-tolerated in the QW schedule and some anti-tumor activity was observed in heavily pretreated pts with EFNA4 unselected advanced malignancies. However, in the expansion cohort (Part 2) at RP2D in TNBC no objective responses were observed regardless of EFNA4 expression. Final safety, efficacy, expression and PK data will be reported at the meeting. Clinical trial information: NCT02078752.
GMI-1271, a novel E-selectin antagonist, in combination with chemotherapy in relapsed/refractory AML.
Authors: DeAngelo Daniel J. , Jonas Brian Andrew , Liesveld Jane , O'Dwyer Michael , Bixby Dale , Advani Anjali S. , Marlton Paula , Magnani John , Thackray Helen M. , Becker Pamela S.
Published: September 2018

2520

Background: GMI-1271 is a novel antagonist of E-selectin (E-sel) that down-regulates cell survival pathways and enhances chemotherapy response. We assessed GMI-1271 plus salvage chemotherapy with mitoxantrone, etoposide, and cytarabine (MEC) for the treatment of patients (pts) with relapsed/refractory (R/R) AML. Methods: A phase (Ph) 1trial in pts with R/R AML escalated GMI-1271 across pharmacologically active doses from 5-20 mg/kg combined with MEC. Safety, tolerability and anti-leukemia activity were assessed. GMI-1271 was given 24 hrs prior, then every 12 hrs during and for 48 hrs post induction/consolidation. Eligible pts had an ECOG score 0-2, received ≤2 prior inductions, WBC < 20K ( < 40K after 2 dose levels), no active CNS disease, and adequate renal/hepatic function. E-sel expression was assessed. After confirming safety and tolerability, a Ph 2 study of GMI-1271 at 10 mg/kg plus MEC was initiated. Results: To date, 47 pts have enrolled (Ph 1 = 19; Ph 2 = 28 of planned 47). The recommended Ph 2 dose is 10 mg/kg based on drug exposure, time over IC50 for E-sel binding, lack of DLT, and clinical outcomes. Ph1/Ph2 combined median age was 55yrs (range 26-84) with 70% male pts. Prior AML history included 26% primary refractory, 36% CR1 < 6 mos; 17% prior SCT; 55% unfavorable cytogenetics (by SWOG). Common Gr 3/4 AEs were febrile neutropenia (36%), sepsis (26%), bacteremia (13%), hypoxia (13%). 30 and 60 d mortality were 0 and 7%, respectively. ORR (CR/CRi/MLFS/PR) was 21/42 evaluable (50%). Remission rate (CR/CRi) was 45%. Observed/expected remission (CR/CRi) ratio was > 2.75 (Estey, Blood 1996). With a median follow-up of 11 mos, the Ph 1 median Leukemia Free Survival was not reached and Overall Survival was 7.6 mos. The median E-sel ligand binding at baseline was 35% of blasts (range, 1-75%) and was higher in those achieving remission. Conclusions: The addition of GMI-1271, a novel E-sel antagonist, to MEC chemotherapy is well tolerated with a high ORR, low induction mortality, and promising initial survival outcomes in pts with R/R AML. Furthermore, the baseline expression of E-sel ligand is predictive of response. Clinical trial information: NCT02306291.
Results of a phase Ib study of ARQ 092 in combination with carboplatin (C) plus paclitaxel (P), or with P in patients (pts) with solid tumors.
Authors: Lakhani Nehal , Tolcher Anthony W. , Rasco Drew W. , Patnaik Amita , O'Rourke Timothy J. , Schwartz Brian E. , Abbadessa Giovanni , Kazakin Julia , Savage Ronald , Wang Yunxia , Chai Feng , Papadopoulos Kyriakos P.
Published: September 2018

2524

Background: ARQ 092 is an oral, potent AKT inhibitor with single agent antitumor activity. P or P+C is the standard therapy or the therapy of choice for pts with various solid tumors. ARQ 092 potentiated antitumor activity of P in in vivo xenograft models, providing the rationale for this study. Methods: This is an open-label, phase Ib study of ARQ 092+C+P (CP Arm) or ARQ 092+P (P Arm) in pts with advanced solid tumors to determine safety and tolerability of these 2 combinations. Blood samples are collected for PK. Results: Enrollment into CP Arm has been completed with 13 pts (15% male; median age 62 years, 4 ovarian, 9 others) being treated in 2 dose cohorts (see table and results below). Enrollment into P Arm is ongoing. Data from P Arm (80 mg/m2 weekly) will be presented during the meeting. In CP Arm, 3 DLTs were observed in 2 pts (both received ARQ 092 at 200 mg BID, 1 day/week) including grade (G) 4 neutrophil count decreased, G 4 thrombocytopenia and G 3 diarrhea. ARQ 092-related adverse events (AEs) in ≥10% pts included diarrhea 69%, fatigue 54%, hyperglycemia 31%, maculopapular rash 31%, nausea 23%, mucosal inflammation 23%, anemia 15%, platelet count decreased 15% and hypokalemia 15%. Paclitaxel- and/or carboplatin-related AEs in ≥10% pts included fatigue 77%, alopecia 62%, thrombocytopenia 39%, platelet count decreased 39%, nausea 31%, lymphocyte count decreased 31%, neutrophil count decreased 31%, white blood cell count decreased 31%, anemia 23%, mucosal inflammation 23%, hypomagnesaemia 23%, peripheral sensory neuropathy 23%, neutropenia 15%, vomiting 15% and hypokalemia 15%. Two ovarian pts previously treated with CP achieved complete response (mutant AKT) and partial response (AKT mutation unknown) respectively and 3 pts (Gastroesophageal, pancreatic, ovarian mixed mullerian) experienced stable diseases for >12 weeks. PK data will be presented during the meeting. Conclusions: Encouraging anticancer activity was demonstrated in heavily pretreated ovarian cancer pts, but full dose CP was not tolerated by most patients. Clinical trial information: NCT02476955. [Table: see text]
Phase 1/2a trial of daily oral BAL101553, a novel tumor checkpoint controller (TCC), in advanced solid tumors.
Authors: Kristeleit Rebecca Sophie , Evans T.R. Jeffry , Ingles Garces Alvaro Henrique , Slater Sarah , Drew Yvette , Devlin Michael-John , Haris Noor R Md , Diamantis Nikolaos , MacDonald Julie , Bachmann Felix , Hannah Alison L. , Anderson Stephanie , Lane Heidi A , Schmitt-Hoffmann Anne , McKernan Phil , Engelhardt Marc Frederick , Greystoke Alastair , Miller Rowan , Plummer Elizabeth R. , Lopez Juanita Suzanne
Published: September 2018

2532

Background: BAL101553 (prodrug of BAL27862) is a small molecule TCC that binds microtubules and promotes tumor cell death by activation of the spindle assembly checkpoint. In a previous study (NCT01397929, Lopez et al. JCO 34, 2016; abstr 2525), 2-h IV infusion on Days 1, 8, 15 (q28d) of BAL101553 up to 80 mg/m2 (maximum administered dose, MAD) showed vascular toxicities, including transient hypertension, which appeared to be Cmax related. The recommended Phase 2 dose (RP2D) was 30 mg/m2 weekly IV. Based on nonclinical models, antiproliferative effects of BAL27862 are driven by AUC. This trial explores whether once daily oral administration of BAL101553 reduces Cmax-related toxicity and improves the therapeutic window (NCT02490800). Methods: Patients (pts) with advanced solid tumors who failed standard therapy, received QD oral BAL101553 (28-d cycles) in a 3+3 dose-escalation design to determine the MTD. Adverse events were assessed by CTCAEv4 grade (G); tumor response by RECIST 1.1; serial PK on Day 1 of Cycles 1 and 2. Results: In the ongoing study, 19 pts (9M/10F; median age 67 y) received doses of 2, 4, 8, 16 or 30 mg oral BAL101553 QD. The MAD was 30 mg with DLTs of reversible G2 hallucination and asymptomatic, reversible G3 electrolyte imbalances. No DLTs were observed at ≤ 16 mg. Dosing is ongoing between 16 and 30 mg QD to determine the MTD. BAL27862 exposures after oral QD dosing of BAL101553 compared to weekly 2-h infusions suggested high relative oral bioavailability. The BAL27862 weekly AUC at the oral MAD (30 mg QD) compared to the RP2D of 30 mg/m2 for 2-h IV was more than 5-fold higher (19,656 vs 3,584 ng*h/mL) and Cmax was 1.5-fold lower (171 vs 266 ng/mL). Both Cmaxand AUC were dose-proportional, with low/moderate variability. Oral BAL101553 had no effects on blood pressure and showed no vascular toxicity. 5 pts had stable disease (2 pts [cholangiocarcinoma, neuroendocrine pancreatic cancer] > 4 cycles). Conclusions: Daily oral BAL101553 enables higher weekly exposures of BAL27862 with lower Cmax levels compared with a 2-h weekly infusion, due to the absence of Cmax related vascular toxicity. Doses up to 16 mg QD are well tolerated. The MAD has been identified as 30 mg QD; definition of the MTD is ongoing. Clinical trial information: NCT02490800.
Whole exome sequencing (WES) of multiple spatially distinct biopsies from single metastatic lesions to evaluate tumour heterogeneity and identify actionable truncal mutations (ATMs) in patients (pts) with advanced solid malignancies using a radiologically-guided single-pass percutaneous technique.
Authors: Heong Valerie , Wee Bernard , Goh Shane , Tay Darwin , Lee Xiao Wen , Soo Ross A. , Lim Joline Si Jing , Sundar Raghav , Chee Cheng Ean , Lee Soo-Chin , Ow Samuel Guan Wei , Goh Boon C. , Yong Wei-Peng , Wong Andrea Li Ann , Gopinathan Anil , Lim Diana , Pang Brendan , Feroz Mohammad , Soong Richie Chuan Teck , Tan David Shao Peng
Published: September 2018

2550

Background: Genomic profiling of single core biopsies (bx) are confounded intratumoral heterogeneity, resulting in sampling bias. We explored the use of a novel technique to obtain multiple bx from single metastatic lesion in pts to evaluate heterogeneity and identify therapeutic ATM. Methods: 15 pts (5 NSCLC; 3 ovarian; 2 colon, 2 uterine and 1 breast, cervix and HCC) with biopsiable lesions were identified. Using a single pass radiologically guided percutaneous bx technique, we obtained multiple spatially distinct core bx samples from a single metastatic lesion. Each bx underwent DNA extraction and WES using the NextSeq500. Results: Median of 4 core bx were obtained from each lesion. Complication rate utilizing this technique was 0%. 2 pts were omitted from analysis due to poor quality DNA with 13 pts successfully sequenced. In 1 pt, only 2 of 4 cores were successfully sequenced. The median amounts of total and non-synonymous variants were 137 (27-1286) and 66 (10-649) respectively. The median (range) filtered variants detected in 1/4, 2/4, 3/4, and 4/4 bx cores was 63(16-91)%, 5(1-65)%, 4(0-30)% and 26(0-63)% respectively, suggesting significant subclonal diversity within a single lesion. ATMs were identitified in 8/13 pts. 4/13 pts (31%) had no ATM across all 4 cores. 3 pts received therapy with inhibitors targeting ATMs. A pt with AKT1_E17K ATM received an AKT inhibitor with 21% tumour shrinkage and PFS 6.1 mths. 2 NSCLC pts harbouring an EGFR_T790M ATM were treated with an EGFRT790M specific TKI. 1 withdrew due to toxicity after 2mths and another had PFS > 16.5 mths. Tumour mutational burden (TMB) was consistent across multiple bx from each lesion. A NSCLC pt with the highest TMB received a checkpoint inhibitor with ongoing > 4 mths stable disease. Conclusions: Utilizing a single pass radiologically guided techniqueto obtainmultiple bx is feasible, safe and informative. This allows reconstruction of a tumour’s subclonal genomic architecture, providing insights into mutational heterogeneity and help guide therapy.
Phase I study of the combination of balixafortide (CXCR4 inhibitor) and eribulin in HER2-negative metastatic breast cancer (MBC) patients (pts).
Authors: Gil-Martin Marta , Gomez Pardo Patricia , Lopez-Tarruella Sara , Manso Luis , Perez-Fidalgo Jose Alejandro , Ademuyiwa Foluso Olabisi , Mayer Ingrid A. , Pluard Timothy J. , Martinez Garcia Maria , Kaufman Peter A. , Vahdat Linda T. , Hooftman Leon W. , Romagnoli Barbara , Hernando Cristina , Weilbaecher Katherine N. , Ciruelos Eva M. , Martin Miguel , Pernas Simon Sonia , Cortes Javier
Published: September 2018

2555

Background: Balixafortide (POL6326) is a cyclic peptide and a potent, selective antagonist of the chemokine receptor CXCR4. Evidence suggests that CXCR4 inhibition interferes with the tumor-protective microenvironment and sensitizes tumor cells to chemotherapy. The combination of balixafortide (B) and eribulin (E) was safe with early signs of efficacy in the dose escalation part of this study. Methods: The expanded cohort of thisopen label phase I study was designed to assess the anti-tumor activity, safety and pharmacokinetics of the addition of the recommended phase 2 dose (RP2D) of B to E in pts with MBC and with any CXCR4 expression level at the tumor site. Patients received E (1.4 mg/m2) on days 2 and 9, flanked by B (5.5 mg/kg) on days 1-3, and 8-10 of 21-day cycles. Results: 24 pts with relapsed MBC (median age 59 [33-82]) were enrolled in the expanded cohort. Median number of prior chemotherapies for MBC was 2 (range 1-3). 20/24 (83%) pts were ER and/or PR positive; 3/24 (13%) pts had TNBC. Objective response rate (ORR) was 33%. 8/24 (33%) pts achieved a partial response and 4/24 (17%) pts had meaningful (≥ 6 months) stable disease for a Clinical Benefit Ratio of 50%. Median duration of treatment was 15.3 weeks (range 5-40) with 11 pts still on treatment. The most common Gr 3-4 adverse events were neutropenia (9/24, 38%) and leucopenia (3/24, 13%); 2 pts had febrile neutropenia and 1 patient died from sepsis. 15/24 (63%) pts experienced histamine-like infusion reactions related to B that were manageable with anti-histamines. Conclusions: The therapeutic activity of this treatment regimen appears promising with an ORR of 33% in patients with advanced MBC. B (5.5 mg/kg) can be combined safely with E (1.4 mg/m2) and the safety profile resembles E monotherapy as previously reported. This is the first study of the treatment combination of E with B in relapsed MBC pts. Further confirmatory studies are being considered. Clinical trial information: NCT01837095.
Exposure-efficacy and safety analysis of durvalumab in patients with urothelial carcinoma (UC) and other solid tumors.
Authors: Jin Chaoyu , Zheng Yanan , Jin Xiaoping , Mukhopadhyay Pralay , Gupta Ashok Kumar , Dennis Phillip A. , Ben Yong , Roskos Lorin , Narwal Rajesh
Published: September 2018

2568

Background: Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD-80. The objective of this analysis was to evaluate the relationship between durvalumab PK exposure with efficacy and safety following 10 mg/kg Q2W durvalumab. Methods: Data from Study 1108 (Phase 1/2; all tumor types) and ATLANTIC (Phase 2; NSCLC) were used for exposure-safety analysis for Study 1108 UC cohort, Study 1108 all patients and ATLANTIC patients, respectively, whereas the exposure-efficacy analysis was performed using data from Study 1108 UC cohort. The observed PK exposure metrics included PK concentrations after the first, second or steady state doses. Efficacy endpoints used were objective response rate (ORR) and best percentage change in target lesion from baseline per BICR assessment. Safety endpoints included Grade 3+ AE (any AE, drug-related AE, AESI, and drug-related AESI) and AE leading to treatment discontinuation. Results: Overall, no association of PK exposure with efficacy or safety was observed. Distribution of PK metrics were similar between responders and non-responders. The probability of objective response was similar in all quartiles of exposure (p-value ranged from 0.37 to 0.67; n = 96) with no obvious trends between PK exposures and change in tumor size. For Grade 3+ AE (all types) and AE leading to treatment discontinuation, higher PK exposure was not associated with an increased risk of AE (p-value ranged from < 0.00005 to 0.88; n = 158, 929 and 434 for 1108 UC cohort, 1108 all patients and ATLANTIC all patients, respectively). A few inverse trends were observed, likely due to confounding effect of ECOG or albumin since covariate analysis demonstrated that both variables correlated with PK and AEs. In addition, the association of ECOG and albumin versus PK exposure were also observed in the population PK modeling. Conclusions: The exposure-efficacy and exposure-safety analyses suggested that 10 mg/kg IV Q2W regimen was an appropriate dose for durvalumab as single agent in UC patients. Overall, no relationship of PK exposure with either the efficacy or safety was observed following 10 mg/kg IV Q2W regimen. Clinical trial information: NCT02087423 and NCT01693562.
A phase IB study of the combination of selumetinib (AZD6244, ARRY-142886) and cyclosporin A (CsA) in patients with advanced solid tumors with an expansion cohort in metastatic colorectal cancer (mCRC).
Authors: Krishnamurthy Anuradha , Dasari A. , Noonan Anne M. , Mehnert Janice M. , Lockhart Albert C. , Stein Mark N. , Sanoff Hanna Kelly , Lee James J. , Hansen Aaron Richard , Malhotra Usha , Rippke Sarah , Davis Sarah Lindsey , Messersmith Wells A. , Eckhardt S. Gail , Lieu Christopher Hanyoung
Published: September 2018

2587

Background: MEK inhibition is of interest in cancer drug development. However, better strategies are needed to overcome acquired resistance to MEK inhibitors. Preclinical studies have shown Wnt pathway overexpression in KRAS mutant cell lines resistant to the MEK inhibitor, selumetinib. The combination of selumetinib and cyclosporin A (CsA), a non-canonical Wnt pathway modulator, demonstrated antitumor activity in patient-derived xenograft (PDX) models. We conducted an NCI CTEP-approved Phase I/IB trial (NCI # 9571/COMIRB # 13-2628/NCT02188264) of selumetinib and CsA combination. Biomarkers of response are being co-developed. Methods: Patients with advanced solid tumors were treated with the combination of selumetinib and CsA in dose escalation followed by an expansion cohort in patients with irinotecan and oxaliplatin-refractory mCRC (n = 20). The expansion cohort utilized a selumetinib “run-in” to evaluate efficacy in RAS-WT and RAS-MT mCRC to identify those patients most likely to respond to the combination. Results: As of January 2017, 18 patients were enrolled in the dose escalation phase and 20 patients were enrolled in the dose expansion phase. The most common adverse events and grade 3/4 toxicities were rash, hypertension, and edema. Three DLTs - Grade 3 hypertension, rash and increased creatinine were reported. The maximum tolerated dose was identified as selumetinib 75 mg BID and CsA 2 mg/kg BID on a 28-day cycle. The selumetinib “run-in” did not favor a specific RAS type. Two partial responses were noted. Sixteen patients had stable disease, and 6 patients had progression of disease as their best response to therapy. Conclusions: Selumetinib in combination with cyclosporin A appears to be well tolerated with evidence of activity in mCRC. Tumor response data are currently being updated. FZD will be evaluated as a potential biomarker of response. Clinical trial information: NCT02188264.
Open label, non-randomized, multi-cohort pilot study of genetically engineered NY-ESO-1 specific NY-ESO-1c259t in HLA-A2+ patients with synovial sarcoma (NCT01343043).
Authors: Mackall Crystal , Tap William D. , Glod John , Druta Mihaela , Chow Warren Allen , Araujo Dejka M. , Grupp Stephan A. , Van Tine Brian Andrew , Chagin Karen , Van Winkle Erin , Kari Gabor , Trivedi Trupti , Norry Elliot , Holdich Tom , Bartlett-Pandite Arundathy N. , Amado Rafael G. , D'Angelo Sandra P.
Published: September 2018

3000

Background: NY-ESO-1 is expressed in ~70% of synovial sarcomas (SS). NY-ESO-1c259T cells recognizing an NY-ESO-1 derived peptide complexed with HLA-A*02 are being studied in SS. Methods: Eligible patients (pt) are HLA-A*02:01, 02:05 or 02:06, with unresectable, metastatic or recurrent SS expressing NY-ESO-1. Primary endpoint of ORR (CR+PR) is evaluated in high (≥ 50% tumor cells express 2+/3+) and low (≥ 1+ in ≥ 1% cells, not exceeding 2+/3+ in ≥ 50% cells) NY-ESO-1 expressers with different lymphodepleting regimens. Secondary endpoints are safety, DOR, PFS, OS, and gene-marked cell persistence. Lymphocytes are obtained by leukapheresis, isolated, activated, transduced to express NY-ESO-1c259T, and expanded. Target dose is 1–6 × 109cells. Disease is assessed at wk 4, 8 and 12 post-T-cell infusion, and then every 3 months. Results: 34 pt have been enrolled with 24 treated. 50% are male; median age is 30 yr (range 15 – 73). 12/15 pt in cohort 1 were treated. ORR was 50% (1 CR; 5 PR). Time to response was 6 wk (range 4-9) and median DOR 31 wk (range 13-72). Cohort 3 was closed due to only 1 PR out of 5 pt. Evaluation is ongoing in cohorts 2 (6 enrolled; 5 treated) and 4 (8 enrolled; 2 treated) as of 1/9/17. The most common AE are leukopenia (96%), nausea and pyrexia (88%), neutropenia (88%), lymphopenia (83%), anemia (79%), and thrombocytopenia (79%). 11 events of CRS were reported (3 G3; 1 G4), with no events of seizure, cerebral edema or fatal neurotoxicity; all resolved with supportive therapy. One fatal SAE (bone marrow failure) occurred in cohort 2; investigations have not identified a mechanism by which NY-ESO-1c259T may have caused this event. Conclusions: NY-ESO-1c259T has promising efficacy and acceptable safety. CRS is not associated with severe neurotoxicity and appears manageable with appropriate supportive care. Cohort 3 data indicate that Flu may be important for efficacy. Efficacy and safety data will be further evaluated and presented. Clinical trial information: NCT01343043. [Table: see text]
CX-1158-101: A first-in-human phase 1 study of CB-1158, a small molecule inhibitor of arginase, as monotherapy and in combination with an anti-PD-1 checkpoint inhibitor in patients (pts) with solid tumors.
Authors: Papadopoulos Kyriakos P. , Tsai Frank Yung-Chin , Bauer Todd Michael , Muigai Lucas , Liang Yu , Bennett Mark K. , Orford Keith W. , Fu Siqing
Published: September 2018

3005

Background: Arginase is secreted by myeloid-derived suppressor cells (MDSCs) and polymorphonuclear cells (PMNs) in the tumor microenvironment, depleting arginine, an amino acid required for T-cell activation and proliferation. CB-1158 is an oral small molecule inhibitor of arginase. CB-1158 reverses PMN- and MDSC-mediated suppression of T-cells in ex vivo human models, and increases plasma and tumor arginine levels in mouse syngeneic tumor models leading to increased pro-inflammatory markers and activated CD8 T-cells in the tumor. CB-1158 has single agent efficacy in mouse tumor models and synergistically enhances the antitumor efficacy of checkpoint inhibitors. Methods: This is an ongoing phase 1 study to evaluate safety and tolerability of CB-1158 as a monotherapy and in combination with anti-PD-1 in pts with solid tumors. Pharmacokinetics (PK), anti-tumor effects, and biomarkers, including plasma arginine, arginase activity, and effects on immune function in blood and in tumors will be evaluated. CB-1158 was administered BID orally in 28-day cycles. Escalating doses were administered to cohorts for safety evaluation. Additional pts were enrolled at dose levels determined to be safe to support biomarker objectives. Results: Nine pts have been enrolled across two monotherapy dose escalation cohorts (50 and 100 mg) and biomarker cohorts. CB-1158 was rapidly absorbed (Tmax = 4 h) and was cleared with a half-life of 6 h. At doses of 50 and 100 mg, steady-state plasma trough levels were 1.6 and 4.5 µM, sufficient to achieve > 90% arginase inhibition, and plasma arginine levels increased 2.4- and 4-fold, respectively. CB-1158 has been well tolerated with no DLTs or drug-related Grade 3 AEs. Dose escalation is ongoing and updated safety, PK and biomarker data will be presented. Conclusions: CB-1158 is a first-in-class inhibitor of the myeloid-derived immunosuppressive enzyme arginase. CB-1158 has been well tolerated and achieves on-target inhibition resulting in increases in plasma arginine, an amino acid required for T-cell immune responses. Clinical trial information: NCT02903914.
Loss-of-function of PBRM1 to predict response to anti-PD-1/PD-L1 therapy in metastatic renal cell carcinoma.
Authors: Miao Diana , Margolis Claire , Martini Dylan , Mullane Stephanie Anne , Cullen Dana , Horak Christine , Wind-Rotolo Megan , Hellmann Matthew David , Voss Martin Henner , Motzer Robert J. , Norton Craig , Signoretti Sabina , Snyder Charen Alexandra , Van Allen Eliezer Mendel , Choueiri Toni K.
Published: September 2018

3016

Background: Immune checkpoint inhibitors targeting programmed cell death-1 (PD-1) substantially improve patient survival in clear-cell renal cell carcinoma (ccRCC), but predictive biomarkers for efficacy have not yet been identified. Methods: We analyzed whole exome sequencing (WES) from a clinical trial of anti-PD-1 monotherapy (nivolumab) for ccRCC (N = 34) to discover genomic predictors of response to immune checkpoint therapy, and validated our findings in 28 ccRCC patients from 2 institutions treated with anti-PD-1 or anti-PD-L1 therapies. We defined 3 response groups: clinical benefit (CB) – complete or partial response by RECIST or stable disease with objective decrease in tumor burden and progression free survival (PFS) > 6 months - and no clinical benefit (NCB) – progressive disease with PFS < 3 months, with all other patients in intermediate benefit (IB). We further validated our findings in WES from 212 melanoma patients treated with immune checkpoint therapies in 3 published cohorts. Results: Biallelic loss of the chromatin remodeling subunit PBRM1, mutated in 34/62 (55%) patients across both cohorts and up to 41% of ccRCC overall, was the only gene mutation associated with CB in both the training (p = 0.0064; Pearson’s chi-squared) and validation cohorts (p = 0.043), and predicted both PFS and overall survival (OS) (p = 0.042 and 0.014, respectively; Kaplan-Meier). In 212 melanomas, truncating alterations in ARID2 – a closely related chromatin remodeler - were also enriched in responders after correcting for tumor mutational burden (p = 0.036), and having a truncating alteration in either PBRM1 or ARID2 significantly predicted overall survival (p = 0.022). In this ccRCC cohort, tumor mutational burden and loss of antigen presentation machinery were not associated with CB or NCB. Conclusions: Loss of chromatin remodeling subunits may impact response to immune checkpoint therapy in both ccRCC and melanoma. Further study in larger cohorts of immunotherapy-treated patients and functional characterization of ARID2 and PBRM1 in the context of the tumor-immune microenvironment will help to determine potential for further biomarker development.
Expression quantitative trait loci (eQTLs) as germline determinants of melanoma immunotherapy response.
Authors: Ferguson Robert , Simpson Danny , Martinez Carlos N. , Vogelsang Matjaz , Kazlow Esther , Moran Una , Weber Jeffrey S. , Sullivan Ryan J. , Flaherty Keith , Pavlick Anna C. , Ribas Antoni , Osman Iman , Kirchhoff Tomas
Published: September 2018

3017

Background: Approximately 40-60% of metastatic cutaneous melanoma (CM) patients do not respond to the current immunotherapy (IT) regimens, pointing to other yet unknown factors conferring IT resistance. Based on our recent findings showing that germline expression quantitative trait loci (eQTLs) in immune pathways associate with overall CM survival, in this study we tested whether germline immune-specific eQTLs also impact IT outcomes in CM. Methods: By interrogating a healthy twin cohort expression dataset (MuTHER), we have identified 50 eQTLs most significantly associated with the expression of 265 immune genes. Using the MassARRAY system, these 50 SNPs were genotyped in 138 anti-CTLA-4 treated patients, 59 PD-1 treated patients and 38 patients from combined (COMBO) treatments collected from multi-institutional collaborations. To test the association of SNPs with IT response, logistic regression was performed for each treatment group adjusting by demographic and clinical covariates. Results: We found significant associations with COMBO IT resistance for rs6673928 (OR = 4.249, p = 0.0167), an eQTL in IL10/IL19 which we have recently identified for association with melanoma survival; interestingly, it is a previously established locus associated with the risk of several autoimmune diseases. Additionally, we also identified eQTLs that are associated with IT sensitivity: rs4848306 in IL1-β with resistance to anti-CTLA-4 (OR = 0.373, p = 0.000733) and rs2071304 in SPI1with resistance to anti-PD-1 (OR = 0.3328, p = 0.0271). Conclusions: In this study we report that rs6673928, an eQTL from the IL19/IL10 locus previously shown to predict autoimmunity risk and CM survival, is also a surrogate marker of response to COMBO IT. The associations of rs6673928 with both IT response and CM survival indicate a strong relationship between interleukin pathways and the level of tumor immunogenicity. In addition to its apparent function in immune response, the putative multi-faceted role of this locus in predicting better survival and IT outcomes indicates high potential as a novel clinical target. Additional genetic and functional validation of these findings is currently underway in a large collaborative setting.
FDA analysis of patients with baseline autoimmune diseases treated with PD-1/PD-L1 immunotherapy agents.
Authors: Weinstock Chana , Singh Harpreet , Maher Virginia Ellen , Kim Geoffrey , Pazdur Richard
Published: September 2018

3018

Background: With FDA approval of three novel agents targeting the PD-L1/PD-1 checkpoint pathway in multiple tumor types, use of these agents in the clinical setting is becoming increasingly common. However, little is published on their use in patients with a history of autoimmune diseases. We therefore aimed to collect safety data on patients with a history of autoimmune diseases treated with PD-1/PD-L1 immunotherapy agents in a clinical trial setting. Methods: Data on patients with a history of autoimmune disease were collected for four different PD-1/PD-L1 immunotherapy agents. Information collected included name of autoimmune disease, corticosteroid dependency at baseline, duration of dosing, immune-related adverse events (iRAEs) and worsening of underlying autoimmune disease. Results: In total, 552 patients enrolled in 22 clinical trials of PD-1/PD-L1 immunotherapy agents were identified with a history of autoimmune disease. None were known to be dependent on systemic corticosteroids at baseline. The most common autoimmune diseases identified were thyroid disorder (n = 188), psoriasis (n = 70), and vitiligo (n = 44). For the four agents identified, mean duration of dosing was 183, 187, 196, and 145 days. Worsening of underlying autoimmune disease occurred in 16%, 6%, 13% and 6%. There were two grade 4 cases of hyperglycemia in patients with diabetes, three cases each of grade 3 AEs related to the underlying disorder in patients with psoriasis, interstitial lung disease, and hypothyroidism, and one grade 3 AE in a patient related to ankylosing spondylitis.For two of these agents, data were available on the development of grade 1-4 irAEs (per investigator) that required treatment with systemic steroids, which occurred in 8% and 9% of patients. Conclusions: Clinical trial data demonstrates relative safety of the use of PD-1/PD-L1 immunotherapy agents in patients with a history of autoimmune disease compared to their use in patients without such history. No consistent pattern of worsening of baseline autoimmune disease was identified. These results should be interpreted with caution, as diagnostic method and clinical manifestations of reported baseline autoimmune conditions are not known.
Product characteristics associated with in vivo expansion of anti-CD19 CAR T cells in patients treated with axicabtagene ciloleucel (axi-cel).
Authors: Locke Frederick Lundry , Rossi John , Neelapu Sattva Swarup , Xue Allen , Better Marc , Zhang Xiao , Ghobadi Armin , Lekakis Lazaros J. , Miklos David Bernard , Jacobson Caron Alyce , Braunschweig Ira , Oluwole Olalekan O. , Siddiqi Tanya , Lin Yi , Timmerman John , Reagan Patrick Michael , Navale Lynn , Go William Y. , Wiezorek Jeffrey S. , Bot Adrian
Published: September 2018

3023

Background: Axi-cel (formerly KTE-C19) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy. ZUMA-1 is a multicenter, registrational trial of axi-cel in patients (pts) with refractory aggressive non-Hodgkin lymphoma. In a prespecified interim analysis, ZUMA-1 met its primary endpoint, with a 76% objective response rate and a 47% complete response rate ( Blood 2016;128:LBA-6). Post-treatment CAR T cell blood levels were associated with objective response. Here, we describe novel associations between product characteristics and CAR T cell levels in pts. Methods: CAR T cell characteristics in axi-cel produced from 62 pts were analyzed by flow cytometry and modeled against CAR T cell levels. In vivo CAR T cell levels were measured by qPCR. T cell expansion during production (fold expansion/total days in culture) was compared with CAR T cell blood levels, using a partition analysis with expansion rates of ≥1 vs < 1. Wilcoxon 2-sample test and linear regression were used. Results: Axi-cel contained CCR7+ T cells (median, 42%; range, 15–73%), with naïve (CD45RA+/CCR7+; median, 12%; range, 1–57%), central memory (CD45RA−/CCR7+; median, 29%; range, 12–49%) phenotypes, and more differentiated CCR7− effector memory and effector T cells. On infusion, CAR T cells expanded rapidly, reaching peak levels within 2 weeks (median, 43 cells/μL; range, 1–1513), and were also measurable in all pts at 1 month (median, 2 cells/μL; range, 0.03–89). The CCR7+/CCR7− T cell ratio in axi-cel associated positively with peak ( P =0.001) and cumulative ( P =0.003) CAR T cell levels through 1 month. Axi-cel lots that expanded more rapidly during production (≥1.0-fold/d; n = 18/62) associated with higher cumulative levels of CAR T cells ( P =0.03). Other product characteristics, eg, CD4/CD8 ratio or number of infused T cells, were not significantly associated with CAR T cell blood levels. Conclusions: An association was observed between CAR T cell expansion in vivo and both the T cell growth rate during production and product cell phenotype pretreatment. A key attribute of axi-cel product was the presence of CCR7+ naïve/central memory T cells, without upfront T cell subset selection. Clinical trial information: NCT02348216.