bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I trial of a novel stapled peptide ALRN-6924 disrupting MDMX- and MDM2-mediated inhibition of WT p53 in patients with solid tumors and lymphomas.
Authors: Meric-Bernstam Funda , Saleh Mansoor N. , Infante Jeffrey R. , Goel Sanjay , Falchook Gerald Steven , Shapiro Geoffrey , Chung Ki Y , Conry Robert Martin , Hong David S. , Wang Judy Sing-Zan , Steidl Ulrich , Walensky Loren D. , Guerlavais Vincent , Payton Marie , Annis D. Allen , Aivado Manuel , Patel Manish R.
Published: September 2018

2505

Background: ALRN-6924 is a cell-penetrating stapled alpha-helical peptide designed to equipotently disrupt the interaction between the p53 tumor suppressor protein and its endogenous inhibitors, murine double minute X (MDMX) and 2 (MDM2). For TP53 wild-type (WT) tumors, pharmacological disruption of this interaction offers a means to restore p53-dependent cell cycle arrest and apoptosis, resulting in antitumor efficacy via a novel mechanism. Methods: The study evaluated safety, PK, PD and anti-tumor effects of ALRN-6924 in patients (pts) with advanced solid tumors or lymphomas in a standard 3+3 design. Pts received ALRN-6924 IV once weekly for 3 consecutive wks on a 28-day cycle (arm A), or 2/wk for 2 consecutive wks on a 21-day cycle (arm B). Results: As of Dec 2016, 69 pts were enrolled with median age 61 yrs (25-78). Pts received a median of 2 (1-19) cycles in arm A [0.16-4.4 mg/kg] and 3 (1-19) cycles in arm B [0.32-2.7 mg/kg]. ALRN-6924 showed a t1/2 of 5.5 hours, dose-dependent PK, and an increase in serum macrophage inhibitory cytokine-1. Treatment-related AEs seen in 96% of pts were primarily grade 1 and 2; most frequent were GI side effects, fatigue, anemia, and headache. DLTs were G3 fatigue at 3.1 mg/kg, and G3 hypotension, G3 alkaline phosphatase elevation, G3 anemia and G4 neutropenia at 4.4 mg/kg all in 5 pts in arm A. No G3/4 thrombocytopenia was observed. All DLTs resolved with dose hold. Infusion-related reactions were seen in 7 pts, with 3 treatment discontinuations. The RP2D was determined to be at MTD: 3.1 mg/kg QW for 3 wks every 28 days. In 55 pts evaluable for efficacy, disease control rate (DCR) was 45%, including 2 CR (Peripheral T-cell Lymphoma [PTCL], Merkel Cell Carcinoma), 2 PRs (Colorectal Cancer, Liposarcoma) and 21 pts with SD. In WT TP53 pts who initiated ALRN-6924 at ≥0.8 mg/kg, DCR was 57%. 9 pts remain on treatment post data cutoff including 3 pts exceeding 1 year of treatment. Conclusions: ALRN-6924 was well tolerated and demonstrated intriguing anti-tumor activity in this first-in-human phase I trial. An expansion phase IIa cohort in PTCL opened in August 2016 using 3.1 mg/kg (arm A) and is currently enrolling. Clinical trial information: NCT02264613.
A first-in-human dose phase 1 study of LY3009120 in advanced cancer patients.
Authors: Hong David S. , Hollebecque Antoine , Gordon Michael S. , Flaherty Keith T. , Shapiro Geoffrey , Rodon Jordi , Millward Michael , Ramdas Nina , Zhang Wei , Gao Ling , Sykes Amanda , Willard Melinda D. , Yu Danni , Schade Andrew , Flynn Daniel Lee , Kaufman Michael , Peng Sheng-Bin , Conti Ilaria , Tiu Ramon Velasquez , Sullivan Ryan J.
Published: September 2018

2507

Background: LY3009120, a pan-Raf and dimer inhibitor, demonstrates inhibition of phospho-Mek/Erk and tumor growth inhibition in several non-clinical cancer models with BRAF, NRAS, or KRAS mutations. This is the first-in-human phase 1 study of LY3009120 in patients (pts) with advanced cancer. Methods: The safety and tolerability of LY3009120 was evaluated in pts with cancer aged 18 years or older who had an ECOG performance status ≤1, at least 1 unidimensionally measurable lesion (RECIST 1.1), and adequate organ function (NCT02014116; I6X-MC-JBDA; Eli Lilly & Co.). The study sought to determine a recommended phase 2 dose using the toxicity band method and the safety, pharmacokinetic, and preliminary efficacy of LY3009120. Pharmacodynamic (PD) biomarkers, including pERK, p27 and Ki67, were evaluated in tumor tissue. The dose escalation phase evaluated dosages from 50 mg to 500 mg by mouth twice daily in pts with advanced cancers. Results: 34 pts (3 at 50 mg, 4 at 100 mg, 3 at 200 mg, 15 at 300 mg, 7 at 400 mg, and 2 at 500 mg) in dose escalation and 1 pt in dose expansion (1 at 300 mg) received at least one dose of LY3009120 by January 2, 2016 (median age = 47.4 yrs, range: 26-82 ). Most pts had a gene mutation (BRAF, n = 7; N/KRAS, n = 18); the most common cancer types included colon (n = 9), non–small cell lung cancer (n = 8), and pancreatic (n = 5). There were 6 dose-limiting toxicities in the dose escalation phase: 2 pts at 300 mg (G3 dermatitis acneiform [n = 1] and G2 blurred vision [n = 1]); 2 pts at 400 mg (G2 increased ALT with G3 hyperbilirubinemia [n = 1] and G3 increased ALT [n = 1]); 2 pts at 500 mg: (G3 arthralgia/myalgia [n = 1] and G3 stomatitis/pain [n = 1]). Based on these data, the maximum tolerated dose for LY3009120 was determined to be 300 mg twice daily. Treatment-emergent adverse events related to LY3009120 occurring in ≥10% of pts included fatigue (34%), nausea (31%), decreased appetite (20%), and dermatitis acneiform (20%) (Grade 1,2). A dose proportional increase in exposure was observed, but not at the 400 mg dose. The best response was stable disease in 5 pts. PD effect by rtPCR was not observed in tested paired tumor samples. Conclusions: LY3009120 is well tolerated at doses of 300 mg twice daily. Updated data from dose expansion will be presented in the meeting. Clinical trial information: NCT02014116.
A first-in-human first-in-class (FIC) trial of the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in patients with advanced solid tumours.
Authors: Halford Sarah E. R. , Jones Paul , Wedge Steve , Hirschberg Sandra , Katugampola Sidath , Veal Gareth , Payne Geoffrey , Bacon Chris , Potter Sarah , Griffin Melanie , Chenard-Poirier Maxime , Petrides George , Holder Graham , Keun Hector C , Banerji Udai , Plummer Elizabeth R.
Published: September 2018

2516

Background: A key metabolic alteration in tumour cells is an increased dependency on the glycolysis, resulting in the production of lactate, which is transported out of cells by MCTs. Inhibition of MCT-1 leads to a profound inhibition of cancer cell growth in preclinical models. AZD3965 is a FIC inhibitor of MCT-1, and we report results from the phase I study of this agent. Methods: Patients with advanced solid tumours were treated with oral (po) AZD3965 at total daily doses of 5-30mg given once (od) and twice daily (bd). Exclusion criteria included a history of retinal or cardiac disease due to preclinical toxicology findings in the eye and heart (which express MCT-1). The primary objectives were to determine the safety, dose limiting toxicities (DLT) and maximum tolerated dose (MTD) of AZD3965. Intensive pharmacokinetic (PK) profiling was performed with subsequent modelling for receptor occupancy. Pharmacodynamic profiling included imaging to detect pH changes and tumour glucose uptake; plasma/urine metabolomics and MCT-1 and MCT-4 tumour expression by immunohistochemistry. Results: 35 patients (20M:15F median age 65) were treated at dose levels 5, 10, 20, and 30mg od and 15 and 10mg bd. AZD3965 was generally well tolerated with nausea and fatigue (CTCAE Gr1-2) the most commonly reported side effects. A single DLT of cardiac troponin rise was observed at 20mg od. Asymptomatic, reversible retinal ERG changes were observed in all but the lowest dose levels, with DLTs observed at doses above 20mg od. PK data indicate exposures in the preclinical efficacy range. Metabolomic changes in urinary lactate and urinary ketones correlate with on-target activity. The increase in urinary ketones is likely to be attributable to the role of MCT1 in physiological ketone transport. Conclusions: The MCT1 inhibitor AZD3965 can be administered to patients at doses which engage the drug target, with a MTD of 20mg od po. DLTs seen were primarily dose dependent, asymptomatic and reversible changes in retinal function, which were an expected on-target effect. Investigation of the activity of AZD3965 is ongoing in tumours known to express MCT1. Clinical trial information: NCT01791595.
A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations.
Authors: Dhawan Mallika Sachdev , Bartelink Imke Heleen , Aggarwal Rahul Raj , Leng Jim , Kelley Robin Kate , Melisko Michelle E. , Ryan Charles J. , Thomas Scott , Munster Pamela N.
Published: September 2018

2527

Background: Talazoparib is a novel PARP inhibitor (PARPi) in clinical development. Synergistic anti-tumor effects of PARPi and chemotherapy have been observed in preclinical models. Overlapping toxicity may limit tolerability in patients with germline DNA repair defects. Methods: In a dose escalation Phase 1 trial, we tested the safety, tolerability, pharmacokinetics (PK), and efficacy of talazoparib and carboplatin in patients with and without germ line mutations. Results: 24 patients with solid tumors were enrolled in 4 cohorts evaluating talazoparib 0.75 or 1 mg daily and carboplatin AUC 1 or 1.5 mg/mL/min 2 or 3 weeks of a 3-week cycle. Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia. Other grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). Post cycle 2 hematologic toxicities required dose delays/reductions in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Of the 4 patients with stable disease beyond 4 months, 3 had somatic BRCA mutations and 1 had a BRIP1 germline mutation suggesting greater benefit in tumors with DNA repair mutations. PK-toxicity modeling suggests that after 3 cycles of carboplatin AUC 1.5 weekly and talazoparib 1 mg daily, the percent decrease in neutrophil counts from baseline was significantly more pronounced in gBRCA carriers; -78% (95% CI: -87 to -68%) vs. non-carriers; -63% (95% CI: -72 to -55%), p-value < 0.001. This modeling also showed that 2-4 fold dose reductions for each drug are needed to improve tolerability of this combination. Pulse dosing of talazoparib may be more tolerable in gBRCA carriers. Conclusions: The combination of carboplatin and talazoparib showed responses in gBRCA carriers but also had increased hematologic toxicity in gBRCA carriers. PK toxicity modeling was used to determine alternate dosing strategies based on carrier status. Clinical trial information: NCT02317874.
Deflexifol (a novel formulation of 5FU): Phase 1 dose escalation study of infusional and bolus schedules after failure of standard treatment.
Authors: Clingan Philip R. , Ackland Stephen P. , Ranson Marie , Brungs Daniel , Aghmesheh Morteza , Tafreshi Ali , Garg Madhu Bala , Parker Suzanne , Henderson Anne , Jokela Rebecca , De Souza Paul L.
Published: September 2018

2529

Background: 5-Fluorouracil (5FU) is administered in combination with leucovorin (LV) to enhance clinical activity. However, simultaneous administration is not feasible as 5FU and LV are chemically incompatible, so the maximum possible interaction for benefit is not achieved Deflexifol, an all in one formulation of 5FU/LV with cyclodextrin (HP-β-CD 100mg/ml, 5-FU 15mg/ml & LV 1mg/ml) at physiological pH, was developed to improve efficacy and tolerance. Methods: A phase I dose-escalation trial to assess the safety, tolerability, MTD and DLT of Deflexifol given in two schedules has been completed. Secondary objectives included the pharmacokinetic (PK) profile and efficacy outcomes. Cohorts of patients with advanced malignancy after failure of standard treatment received Deflexifol as 46-h infusion Q2W or bolus weekly x6 in a standard 3+3 phase I design with no intra-patient dose escalation from dose level 1: 375mg/m² bolus or 1200mg/m² infusional up to dose level 5: 575mg/m² bolus or 3600mg/m² infusional. PK sampling of 5FU and dihydroFU was conducted on all patients to assess PK variability and adequacy of dosing. Results: 40 patients (21 infusional, 19 bolus) with breast (7), colorectal (24), other GI (6) & NSCLC (3) received a total 293 courses of treatment. No > grade 1 toxicity was noted at 375-475 mg/m2 bolus, or at 1200-2400 mg/m2 infusion. The DLT in bolus schedule was grade 3 diarrhea and myelosuppression at 575 mg/m2, with no DLT in the infusion schedule at the maximum dose 3600 mg/m2. The MTD have been established for both treatment arms: bolus 525mg/m²; 46-h infusion 3,600mg/m², with no grade IV toxicity observed. Other grade 3 toxicities were nausea, vomiting, and raised liver function tests. 5FU PK in this mixture is similar to 5FU alone. Encouraging efficacy results were seen with partial response in 1 patient and stable disease in 23 patients. Median PFS was (12.3 wks) and OS was (24.8 wks). Conclusions: Deflexifol has little toxicity and is effective in bolus and infusion schedules at doses equal to or greater than those feasible with 5FU and LV infused separately. A first-line phase II study in combination with oxaliplatin is planned. Clinical trial information: 044867.
FDA analysis of patient enrollment by region in clinical trials for approved oncological indications.
Authors: Kanapuru Bindu , Singh Harpreet , Fashoyin-Aje Lola A. , Myers Adrian , Kim Geoffrey , Farrell Ann , Pazdur Richard
Published: September 2018

2539

Background: Clinical trials are increasingly conducted on a global scale in an effort to accelerate accrual. This analysis attempts to quantify and characterize participants in trials submitted to support approval of drugs for oncology indications by the region of enrollment. Methods: Demographic information was extracted for patients enrolled in clinical trials submitted to the FDA from 2005-2015. Only trials submitted to support approval for malignant solid tumor or hematology indications were included. Countries were grouped into regions for further analysis. A total of 178,024 patients with information regarding age and country were included in this analysis. Results: Forty five percent (80,460) of clinical trial participants were enrolled from Europe, 36% (63,958) from North America (includes U.S.A and Canada) and 8.4% (14,975) from Asia. Countries in Latin America, Middle East/Africa and the Baltic States/Russia enrolled the remainder 10.5% of the patients. Among 99,556 participants < 65 years of age; 38.7% (38,538) were enrolled from North America, 40.5% (40,362) from Europe, 9.7 % (9674) from Asia and 11% from the rest of the regions. Europe enrolled the highest number of cancer patients aged 65 years or older; 51.1% (40,098) compared to 32.4% (25,420) from North America and 6.8 % (5301) from Asia. Conclusions: Majority of patients enrolled into clinical trials submitted for oncology drug approvals were from regions other than North America, with highest number enrolled from Europe particularly in the older age group. While it is interesting to speculate, the reasons for differential enrollment of patients between Europe and North America and the impact of these findings on interpretation of clinical trial results need additional exploration. Analysis of trends over time may be useful to address this issue. [Table: see text]
Safety and pharmacokinetics of crizotinib in patients (pts) with hepatic impairment (HI) and advanced cancer.
Authors: El-Khoueiry Anthony B. , Sarantopoulos John , O'Bryant Cindy L. , Ciombor Kristen Keon , Xu Huiping , O'Gorman Melissa T , Chakrabarti Jayeta , Usari Tiziana , El-Rayes Bassel F.
Published: September 2018

2552

Background: Crizotinib is a kinase inhibitor approved for treating ALK+ and ROS1+ advanced non-small cell lung cancer. Since crizotinib undergoes hepatic metabolism, this phase 1 study evaluated the pharmacokinetics (PK) and safety of crizotinib in pts with liver dysfunction. Methods: Crizotinib-naïve pts with different types of advanced cancer (ALK and ROS1 status unknown), ≥ 18 yr old, and ECOG PS 0–2 were enrolled. Pts were assigned to groups A1 – D based on liver function: normal (A1/A2) = both AST and TB ≤ the upper limit of normal (ULN); mild impairment (B) = AST > ULN and TB ≤ ULN, or TB > 1.0 – 1.5 × ULN; moderate (C1/C2) = TB > 1.5 – 3 × ULN; severe (D) = TB > 3 × ULN. Starting dose was based on HI. Pts in A1 and A2 were matched for weight, age, gender, race and ECOG PS to pts in B and C2, respectively. Study objectives included PK, safety and antitumor activity. Results: 88 pts were enrolled in A1 (n=11), A2 (n=15), B (n=20), C1 (n=10), C2 (n=16) and D (n=16). The geometric means of PK parameters at steady-state (Cycle 2 Day 1) are shown below. 75% of pts experienced treatment-related AEs (TRAEs), 9 (81.8%), 14 (93.3%), 15 (75.0%), 6 (60.0%), 11 (68.8%) and 11 (68.8%) in groups A1, A2, B, C1, C2 and D, respectively. 25% of pts experienced Grade 3/4 TRAEs, 3 (27.3%), 3 (20.0%), 3 (15.0%), 1 (10%), 7 (43.8%), 5 (31.3%) in groups A1, A2, B, C1, C2 and D, respectively. Three (3.4%) pts, all in A2, experienced treatment-related SAEs. Two pts (10%) in B and 1 (6.3%) in C2 required dose reductions for TRAEs. TRAEs associated with permanent discontinuation of treatment occurred in 1 pt in A1, A2, C2 and D. Overall, 3 pts had partial responses with durations of 96, 17 and 17 wks; 25 pts had stable disease. Conclusions: Systemic exposures of crizotinib in pts with mild HI receiving 250 BID and in pts with moderate HI receiving 200 mg BID are comparable with that of pts with normal hepatic function at 250 mg BID. All TRAEs were manageable across the various levels of hepatic function. Clinical trial information: NCT01576406. [Table: see text]
A phase II study of copper-depletion using tetrathiomolybdate (TM) in patients (pts) with breast cancer (BC) at high risk for recurrence: Updated results.
Authors: Sahota Sheena , Kornhauser Naomi , Willis Amy , Ward Maureen M. , Cigler Tessa , Moore Anne , Andreopoulou Eleni , Fitzpatrick Veronica , Schneider Sarah E. , Wiener Alysia , Rubinchik Anna , Lee Sharrell , Lane Maureen E. , Mittal Vivek , Vahdat Linda T.
Published: September 2018

2557

Background: The tumor microenvironment (TME) plays a critical role in the spread of tumors. Bone marrow derived VEGFR2+endothelial progenitor cells (EPCs) and copper-dependent lysyl oxidase (LOX) are key in tumor progression. We hypothesized TM-associated copper depletion inhibits tumor metastases by reducing the number of EPCs and other copper dependent (CD) processes in the pre-metastatic niche. These results are an update with longer follow-up. Methods: Phase II study of BC pts at high risk for recurrence, defined as node+ triple negative (TNBC), stage 3 and 4 with no evidence of disease (NED) were enrolled on a trial of CD with TM. Ceruloplasmin (Cp) levels were maintained between 8-16 mg/dl for two years with an extension phase or until relapse. The primary endpoint was change in EPCs measured by flow cytometry before and during treatment. Secondary endpoints included tolerability, safety, PFS and LOXL-2 levels. Results: 75 pts received 2650 cycles of TM on primary and extension study. The median age is 51 years (range 29-66). Forty-five pts have stage 2/3 BC and 30 with stage 4 NED. TNBC pts were 48% and 40% of pts are stage 4 NED. Median Cp level decreased from 28 to 16 (p < 0.0001) after one cycle. Copper depletion was most efficient in TNBC where Cp levels dropped from 23.5 to 13 after one cycle. TM was well tolerated with grade 3/4 toxicities including: reversible neutropenia (2.3%), febrile neutropenia (0.04%), fatigue (0.2%). Five-year analysis showed a decrease in EPC’s (p = 0.004) and LOXL-2 (p < 0.001). At a median follow-up of 6.9 years, the EFS for 75 pts is 75.6%. PFS for 36 pts with TNBC is 79.2%. EFS for stage 2/3 TNBC is 90% and for stage IV TNBC is 66.7%. Conclusions: TM is safe, well tolerated and appears to affect multiple components of the TME creating an inhospitable environment for tumor progression especially in high risk patients such as TNBC. Randomized trials are warranted, especially in patients at high risk for relapse. Clinical trial information: UL1TR000457.
A first in human phase I study of AZD8186, a potent and selective inhibitor of PI3K in patients with advanced solid tumours as monotherapy and in combination with the dual mTORC1/2 inhibitor vistusertib (AZD2014) or abiraterone acetate.
Authors: Hansen Aaron Richard , Shapiro Geoffrey , Do Khanh T , Kumar Rajiv , Martin-Liberal Juan , Higano Celestia S. , Wisinski Kari Braun , Dean Emma Jane , Heath Elisabeth I. , Rathkopf Dana E. , Linch Mark David , Barry Simon T , Brugger Wolfram , De Bruin Elza , Colebrook Steve , Klinowska Teresa , Mitchell Patrick D , Moorthy Ganesh , De Bono Johann S. , Siu Lillian L.
Published: September 2018

2570

Background: Loss of PTEN function leads to increased PI3Kβ signalling. AZD8186 (AZD) exhibits significant anti-tumour activity in PTEN-deficient preclinical models, particularly when combined with anti-androgens or the dual mTORC1/2 inhibitor vistusertib (AZD2014). Here we report on the dose-finding part of this Phase 1 study. Methods: AZD single agent was administered twice daily (BD) in 3 different schedules (5 days on/ 2 days off, 2 days on/ 5 days off and continuous). Escalating doses of AZD were evaluated in cohorts of 3-6 patients treated until progression, unacceptable toxicity, or consent withdrawal. Accrual is ongoing in the combination arms with vistusertib or abiraterone acetate. Results: As of 16 Jan 2017, 87 patients have received AZD at doses of 30–360 mg BD, with 28 confirmed as PTEN deficient (IHC). The selected RP2D for the 5 days on/2 days off monotherapy schedule is 60 mg BD. PK parameters show that systemic exposures to AZD and its major active metabolite increase in a dose proportional manner. 69 serious adverse events (SAEs) were reported in 31 patients on AZD monotherapy with 23 SAEs considered possibly related to AZD. In the 5/2 schedule: 5 dose limiting toxicities (G3 rash with ≥G2 fever and/or chills) were observed in 5 patients at doses of 120-360mg. Adverse events ≥G1 in > 20% included diarrhoea, nausea, fatigue, LFT elevations and decreased appetite. 20 patients remained on study for > 100 days. Dose-dependent target inhibition has been demonstrated in surrogate tissue (platelets). Evaluation of direct tumour target engagement in paired biopsies is currently ongoing. Preliminary efficacy: Confirmed PRs seen in a CRPC patient (BRCA2 and androgen receptor mutant) treated in combination with vistusertib (on study for 411 days) and in one ongoing monotherapy PTEN-deficient colorectal cancer patient (on study > 329 days). Updated data will be presented. Conclusions: AZD has potential for treatment of PTEN-deficient tumours. Investigation of the safety/tolerability and preliminary efficacy in combination with vistusertib or abiraterone acetate is continuing. Clinical trial information: NCT01884285.
A phase I trial of selective PI3K inhibitor taselisib (tas) plus palbociclib (palb) with and without endocrine therapy incorporating pharmacodynamic (PD) studies in patients (pts) with advanced cancers.
Authors: Lim Joline Si Jing , Asghar Uzma Saddia , Diamantis Nikolaos , Ward Sarah Emily , Parmar Mona , Purchase Beth , Raynaud Florence I. , Swales Karen E , Hrebien Sarah , Hall Emma , Tovey Holly , Bye Hannah , Proszek Paula , Lopez Juanita Suzanne , Turner Alison Joanne , De Bono Johann S. , Banerji Udai , Yap Timothy Anthony , Turner Nicholas C.
Published: September 2018

2573

Background: The phosphatidylinositol 3-kinase (PI3K) pathway is commonly mutated in cancer. Tas is a selective β-isoform-sparing PI3K inhibitor with improved therapeutic index compared to pan-PI3K inhibitors. Palb is a CDK4/6 inhibitor now standard of care in combination with endocrine therapy (ET) in hormone receptor positive breast cancer. Combination of Tas, Palb and ET is synergistic in preclinical models. Methods: This investigator-initiated study investigated safety and tolerability, pharmacokinetics (PK), PD and antitumor activity of Tas+Palb, with addition of ET in dose expansion. Pts were enrolled in 3+3 dose escalation design. Tas was given continuously or 3-weeks-on, 1-week-off (3/1), Palb was given on 3/1 schedule. PD studies included analyses of platelet-rich plasma (PRP) (n = 20) and paired tumor biopsies (n = 5). Serial circulating tumor DNA was monitored in pts with PIK3CA mutations. Results: 24 pts were treated, 22 with Tas+Palb, 2 with Tas+Palb+fulvestrant(ful); M/F 11/13, median lines prior therapy 4. Treatment was well tolerated with mainly G1-2 toxicities. Most frequent G3 toxicities were neutropenia (5/24), thrombocytopenia (5/24) and rash (5/24), with no G4/5 toxicities. Two pts had dose-limiting toxicities (DLT) at DL2. No DLTs were observed at DL4, although pts experienced delayed neutrophil recovery. PK was linear and comparable with monotherapy. At 125mg Palb, significant decreases in pAKT and pGSK3β in PRP confirmed PI3K target inhibition. Two pts with PI3KCA H1047R mutant breast cancers have ongoing RECIST partial response; 1 pt with PIK3CA E542K colorectal cancer had stable disease for 20 weeks. Conclusions: Tas+Palb is well tolerated with evidence of PD and antitumor activity. Dose expansion including recruitment to triplet Tas+Palb+ful and Tas+Palb+letrozole is ongoing with continuous Tas 2mg QD, and Palb 100mg QD on 3/1 schedule, increasing to 125mg after cycle 1 in absence of myelosuppression. Clinical trial information: NCT02389842. [Table: see text]
First-in-human phase 1 study of ETC-159 an oral PORCN inhbitor in patients with advanced solid tumours.
Authors: Ng Matthew , Tan David SP , Subbiah Vivek , Weekes Colin D. , Teneggi Vincenzo , Diermayr Veronica , Ethirajulu Kantharaj , Yeo Pauline , Chen Deborah , Blanchard Stephanie , Nellore Ranjani , Gan Bong Hwa , Yasin Maryam , Lee Lay Hoon , Lee May Ann , Hill Jeffrey , Madan Babita , Virshup David , Matter Alex
Published: September 2018

2584

Background: The Wnt signalling pathway is involved in cellular proliferation, differentiation, migration and implicated in stem cell function in several cancers. ETC-159 is a selective small molecule inhibitor of porcupine, an enzyme required for palmitoylation and secretion of all Wnt ligands. In preclinical studies, ETC-159 induced tumour regression in patient-derived xenograft models. Methods: Open-label, multi-centre study to determine safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics (PD) of ETC-159 given orally, once every other day in a 28d cycle. PD was evaluated by AXIN2 mRNA levels in whole blood and hair follicles and bone turnover by radiological and serum markers. Dose escalation was by ordinal continual reassessment method with a dose-limiting toxicity (DLT) period of 28d. Results: As of 18 Jan 2017, 16 patients (pts) were treated in 6 cohorts at 1 mg (2pts), 2 mg (2pts), 4 mg (3pts), 8 mg (4pts); 16 mg (3pts), and 30 mg (2pts). 80% were male, median age (range) was 55yr (19-68). One DLT was seen at 16 mg due to hyperbilirubinaemia. Adverse events (≥ 20%) were vomiting (32%); anorexia and fatigue (31%); dysgeusia and constipation (25%). ETC-159 Cmax increased with dose with a mean t1/2 of 14 hr. Plasma levels of ETC-159 that inhibited colony formation in vitro were attained from 4 mg onwards. Reduction of whole blood and hair follicle AXIN2 mRNA levels and doubling of serum β-CTX levels was first observed at 4 mg and at C1D15 in some patients. PD modulation increased with dose, consistent with on-target modulation of Wnt signalling. Two pts had β-CTX rise > 1000 pg/mL (reference limit) and a ≥ 5% reduction in bone density by C3D1. Both took vitamin D and calcium supplements and were given i.v. bisphosphonates. No responses were seen but 2 pts (2 mg: colorectal and 4 mg: peritoneal carcinoma) had stable disease for 6 and 8 cycles respectively. Dose-escalation is ongoing at 30 mg. Conclusions: ETC-159 inhibits Wnt signalling at doses that are well tolerated. β-CTX levels increased early on, and in two pts were associated with reduced bone mineral density. Early and regular monitoring of bone turnover is indicated. This study was sponsored by D3 which is funded by NMRC, NRF and BMRC Singapore. Clinical trial information: NCT02521844.
Safety and clinical activity of adenosine A2a receptor (A2aR) antagonist, CPI-444, in anti-PD1/PDL1 treatment-refractory renal cell (RCC) and non-small cell lung cancer (NSCLC) patients.
Authors: Fong Lawrence , Forde Patrick M. , Powderly John D. , Goldman Jonathan Wade , Nemunaitis John J. , Luke Jason John , Hellmann Matthew David , Kummar Shivaani , Doebele Robert Charles , Mahadevan Daruka , Gadgeel Shirish M. , Hughes Brett Gordon Maxwell , Markman Ben , Riese Matthew John , Brody Joshua , Emens Leisha A. , McCaffery Ian , Miller Richard Alan , Laport Ginna
Published: September 2018

3004

Background: Adenosine production in the tumor leads to immunosuppression through A2aR on infiltrating immune cells. CPI-444 is an oral A2aR antagonist with single agent(SA) anti-tumor activity in pre-clinical models. This phase 1/1b clinical trial uses a 2-step adaptive design to evaluate CPI-444 as a SA and in combination (combo) with the anti-PDL1 antibody, atezolizumab (atezo). We report results of RCC and NSCLC cohorts. Methods: Primary objectives: safety, efficacy and to identify optimal dose/schedule. Step 1 utilized 3 SA and 1 combo cohort to select dose/schedule. Step 2 included disease-specific expansion cohorts including RCC and NSCLC. Eligible pts had selected advanced cancers and failed standard therapies including checkpoint inhibitors. Results: 34 pts have enrolled and 25 pts were evaluable for response (Table 1). Median prior regimens: 3 (range,1-5) and most pts were resistant/refractory to anti PD1/PDL1 therapy (R/R). Most common AEs were Gr 1 nausea (n = 3) and pyrexia (n = 3); Gr 3 tachycardia was the only possibly related SAE. The selected Step 2 doses were CPI-444 100mg BID as a SA and in combo with atezo 840mg IV q2 weeks. The disease control rate (DCR, CR+PR+SD; duration 2 mo to > 8 mo) for pts with RCC and NSCLC cohorts were 86% and 50%, (100% and 43% for R/R pts), respectively. DCRs were similar in the SA and combo cohorts. Of 7 evaluable RCC pts, 1 pt has an ongoing PR (SA cohort, > 4 mo) and 5 have ongoing SD, duration 3 mo to > 8 mo (2 SA, 3 combo). Biopsy of the PR pt showed no detectable tumor and infiltration with CD8+ lymphocytes. In 18 evaluable NSCLC pts, 1 PR (PDL1 negative pt) and 8 SD were seen. PRs and SDs were seen in R/R pts and in PDL1 negative pts in both diseases. Conclusions: CPI-444 is well tolerated and shows anti-tumor activity in RCC and NSCLC pts as a SA and in combo. Pts who are R/R to anti PD1/PDL1 therapy and who are PDL1 negative can also benefit. Clinical trial information: NCT02655822. [Table: see text]
The relationship of pharmacodynamics (PD) and pharmacokinetics (PK) to clinical outcomes in a phase I study of OX40 agonistic monoclonal antibody (mAb) PF-04518600 (PF-8600).
Authors: El-Khoueiry Anthony B. , Hamid Omid , Thompson John A. , Ros Willeke , Eskens Ferry , Doi Toshihiko , Hu-Lieskovan Siwen , Chou Jeffrey , Liao Ken , Ganguly Bishu J , Fleener Catherine , Joh Tenshang , Diab Adi
Published: September 2018

3027

Background: PF-8600 is a novel fully human IgG2 agonistic mAb against human OX40, a TNF receptor superfamily member expressed primarily on activated T cells. This ongoing phase 1 study (NCT02315066) is investigating the safety, efficacy, PK and PD of PF-8600 in patients (pts) with solid tumors. Methods: PF-8600 (0.01–10 mg/kg) was given IV every 14d. Expression of free/total OX40 receptor, proliferation marker ki67 and activation markers HLA-DR/CD38 were measured in T cell subsets in peripheral blood by flow cytometry in all pts. CD4, CD8, OX40 and FOXP3 were evaluated in paired tumor biopsies (bx), collected from a subset of pts (≥0.1 mg/kg) at baseline (BL) and Wk6, by immunohistochemistry. Results: As of 21Sep2016, 48 pts with melanoma (n = 14), hepatocellular carcinoma (HCC, n = 19), head and neck squamous cell (n = 6) or renal cell carcinoma (n = 9) enrolled in the dose-escalation cohorts (0.01-3 mg/kg). No immune related adverse events (AE) were reported. The most frequent treatment related AEs in > 3 pts were fatigue (27.1%) and nausea and vomiting (8.3% each); all Gr 1-2. 2 pts had a partial response: melanoma at 0.1 (Pt1) and HCC at 0.3 (Pt2) mg/kg. 25 pts had best ORR (BOR) of stable disease (SD; 3 pts ≥24 wks). A majority of pts at 0.1, 0.3, and 3 mg/kg, including Pt1 and Pt2, had increases in ki67 and HLA-DR/CD38 expression in peripheral CD4+ central memory T cells. Pt1, Pt2 and all pts at ≥0.3 mg/kg had full receptor occupancy. Paired bx were only available from pts with BOR of SD or progressive disease. In 10 pts with available paired tumor bx and defined date of radiographic progression (rPD), longer time to rPD correlated with increases in %OX40+ in bx from BL to Wk6, regardless of dose level, tumor type or prior immunotherapy (R2= 0.52, p = 0.0188); no correlation between rPD and CD4+, CD8+ or FOXP3+ expression changes was observed. Updated efficacy, safety, PK and PD data will be presented. Conclusions: PF-8600 is well tolerated with evidence of single agent efficacy. Initial observations of PD markers that change with treatment and correlate with rPD support efforts to confirm these findings as more clinical outcomes and larger sample sizes become available. Clinical trial information: NCT02315066.
Association of changes in T regulatory cells (Treg) during nivolumab treatment with melanoma outcome.
Authors: Weber Jeffrey S. , Ramakrishnan Rupal , Laino Andressa , Berglund Anders E. , Woods David
Published: September 2018

3031

Background: PD-1 blocking antibodies have significant efficacy in the treatment of melanoma; however, many patients fail to respond and resistance mechanisms remain unknown. We addressed the role of Tregs, an immunosuppressive T-cell population, in patient outcome after treatment with nivolumab. Methods: Peripheral blood mononuclear cells (PBMC) were obtained from patients on trials with nivolumab as adjuvant therapy for resected disease or as treatment for metastatic melanoma. To measure suppression, Tregs were flow-sorted from PBMC and evaluated in allogeneic mixed lymphocyte reactions. Tregs and conventional CD4 T-cells were evaluated for gene expression changes by RNA-sequencing. Treg percentages and phosphorylated STAT3 (pSTAT3) expression were evaluated by flow cytometry. The effects of PD-1 blockade with nivolumab were evaluated in vitro using T-cells from baseline patient PBMC samples. Results: Tregs from responding patients or adjuvant patients without evidence of disease (NED) had reduced suppressive function post-nivolumab (p < 0.05), but no changes were observed in relapsing/non-responding patients; their Tregs were more suppressive than NED/responding Tregs (p < 0.001). NED Tregs had unique gene expression changes and associated pathways post-nivolumab compared to relapsing patient Tregs and conventional CD4 T-cells, including up-regulation of proliferation pathways (q < 8e-19) and downregulation of oxidative phosphorylation (q < 7e-5). NED Tregs had upregulation of pSTAT3 expression post-nivolumab (p < 0.05), which was not observed in relapsing patients. Evaluation of Tregs from patients with active disease also showed upregulation of pSTAT3 in responders (p < 0.05) but not non-responders. The relative increase in Treg pSTAT3 was associated with increased overall survival (R2= 0.49, p < 0.05). In vitro assays using PD-1 blocking antibodies recapitulated the increase in pSTAT3 (p < 0.05) and Treg percentages (p < 0.001), which were diminished with the addition of a STAT3 inhibitor (p < 0.01). Conclusions: These results demonstrate previously unknown roles of decreased Treg suppressive function and induction of STAT3 as biomarkers of patient’s outcome to nivolumab therapy.
Augmentation of adoptive T-cell therapy for Merkel cell carcinoma with avelumab.
Authors: Paulson Kelly Garneski , Perdicchio Maurizio , Kulikauskas Rima , Wagener Felecia , Church Candice , Bui Kieu-Thu , Vandeven Natalie , Thomas Hannah , McAfee Megan , Miller Natalie , Chin Kevin M. , Su Zhen , Greenberg Philip D , Parvathaneni Upendra , Bhatia Shailender , Nghiem Paul , Chapuis Aude
Published: September 2018

3044

Background: 80% of Merkel cell carcinomas (MCCs) are caused by Merkel cell polyomavirus (MCPyV) oncoproteins. Although absent in most cases, abundant MCPyV-specific CD8+ TIL are associated with good MCC outcomes, implying tumor susceptibility to immune attack. Indeed, anti-PD-1 axis blockade has a response rate of 32-56%. However, half of patients do not respond, suggesting a lack of adequate MCPyV-specific T cells and/or tumor evasion from MCC-related reduced HLA expression. We hypothesized the combination of adoptive transfer of MCPyV-specific T cells with HLA upregulation and PD1 axis blockade would be more effective than either approach alone. Methods: 8 adult patients with MCPyV-associated metastatic MCC without pre-existing immune deficiencies were enrolled. The safety and efficacy of ex vivo expanded MCPyV-specific T-cells plus HLA-upregulation (radiation or interferon) with (triple therapy) and without (double therapy) avelumab (mAb against PD-L1, dose 10 mg/kg IV q2weeks) were compared in 2 related phase I/II studies. Results: All 4 patients who received triple therapy (100%) are alive (median follow-up 10 months), and experienced objective responses (RECIST 1.1) with 3 of 4 sustained complete responses (CRs) at last follow-up (longest 13 mo). This compared favorably to outcomes among the 4 patients who received double therapy (3 with progression and 1 CR (25%) for 14 months before progression) and published data for avelumab monotherapy – response rate 32% and CR rate 9% in patients who had failed chemotherapy (Kaufman et al, Lancet Oncol, 2016). Grade 3-4 T cell-related adverse events were similar and anticipated in both groups, including transient lymphopenia (n = 7) and modest cytokine release syndrome lasting < 24 hours, manageable on the general ward (n = 4). No grade 3-4 toxicities were attributed to avelumab. Among patients receiving triple therapy, transferred T cells persisted, and peak frequencies correlated with rate of tumor regression. Conclusions: The combination of MCPyV-specific T cells, avelumab and HLA upregulation is safe and correlative studies suggest avelumab enhances the T cell responses to MCC. This strategy has potential for MCC treatment, and can be readily applied to other solid tumors. Clinical trial information: NCT01758458 and NCT02584829.
Anti-PD-1 monoclonal antibody combined CD3-retronectin activated T cell in heavy-treated renal cell cancer.
Authors: Zhao Lingdi , Li Wei , Yang Yonghao , Zhang Yong , Ren Xiubao , Gao Quanli
Published: September 2018

3047

Background: Metastatic renal cell carcinoma (MRCC) has a poor prognosis after failure of multitargeted tyrosine kinase inhibitors. New immunomodulators, such as anti-programmed death (PD)-1 antibody drugs, have made progress in the treatment of MRCC, but their objective response rate is only about 25%. Therefore, it is important to enhance the response rate of anti-PD-1 therapy. Methods: Patients with MRCC were eligible if they were failed to at least one kinase inhibitors, ECOG PS 0-2. Patients received nivolumab (2mg/kg, q2w) or keytruda ( 2mg/kg, q3w), followed by CD3-retronectin activated T cell, and the total number of CD3-retronectin activated T cell each time was about 5×109/L. The primary objective was to determine the objective response rate, secondary objectives included time to symptom relief, time to efficacy, safety. Results: 8 pts were enrolled (median age 58 [31-79], male 6). Pts had received a median of 2 (1-4) prior regimens. To date there is 2 patients that the efficacy can not be evaluated. The other 6 pts got remission (3 complete remission and 3 partial remission), the median time to efficacy was 10 weeks (6-12 weeks) and the time to symptom relief was 4 weeks (3-6 weeks). There was no grade 3/4 adverse effects. family:'';font-size:12.0000pt;mso-font-kerning:1.0000pt;" > 109/L. The primary objective was to determine the objective response rate, secondary objectives included time to symptom relief, time to efficacy, safety. Conclusions: CD3-retronectin activated T cell might improve the efficacy of anti-PD-1 therapy without increasing the side effects. This combination therapy has many implications in the age of immunotherapy, and should be explored across cancer types. mily:'';font-size:12.0000pt;mso-font-kerning:1.0000pt;" > 109/L. The primary objective was to determine the objective response rate, secondary objectives included time to symptom relief, time to efficacy, safety.
Discovery of COM701, a therapeutic antibody targeting the novel immune checkpoint PVRIG, for the treatment of cancer.
Authors: Liang Spencer , Levy Ofer , Ganguly Sudipto , Kotturi Maya , Vaknin Ilan , Dassa Liat , Azulay Meir , Alteber Zoya , Hansen Kyle , Chan Chris , Leung Ling , Kumar Sandeep , Levin Doron , Safyon Einav , Friedman Tal , Greenwald Shirley , Salomon Ran , Pardoll Drew M. , White Mark , Ophir Eran
Published: September 2018

3074

Background: While inhibitors of CTLA4 and PD1 have emerged as effective cancer therapies, the majority of treated patients do not derive long term benefit. Employing our computational discovery platform, we discovered PVRIG as an immune suppressive molecule expressed on T and NK cells and identified COM701, an antibody (Ab) targeting human PVRIG that enhances T cell function and anti-tumor responses. Methods: Anti-human PVRIG Ab COM701 was identified as an antagonistic Ab that enhanced T cell function in multiple assays. Antagonistic anti-mouse PVRIG Abs and PVRIG deficient (PVRIG-/-) mice were generated and characterized using syngeneic tumor models. Results: PVRIG was induced upon T cell activation, with long term activation leading to the highest expression. PVRL2 was identified as the ligand for PVRIG, placing PVRIG in the DNAM/TIGIT immunoreceptor axis. Compared to normal adjacent tissues, PVRIG and PVRL2 were both induced in the tumor microenvironment of several human cancers. To target PVRIG for therapeutic intervention, we identified COM701, a high affinity Ab that disrupts the interaction of PVRIG with PVRL2. COM701 enhanced CD8 T cell proliferation and IFN-g production in vitro and had an additive or synergistic effect on T cell activation when further combined with an anti-PD1 or anti-TIGIT Ab. Consistent with a checkpoint function for human PVRIG, mouse PVRIG-/- T cells showed increased function compared to wild type T cells. A surrogate antagonistic anti-mPVRIG Ab reduced growth of CT26 and B16 tumors when combined with an anti-PDL1 Ab in vivo. MC38 tumors also grew slower in PVRIG-/- mice compared to wild type mice and ex vivo analysis pointed to functional differences in anti-cancer immunity. Conclusions: We demonstrated that targeting PVRIG with COM701, a high affinity antagonistic Ab, increased human T cell function. We further showed that PVRIG was induced in the tumor microenvironment and that disruption of PVRIG/PVRL2 interaction resulted in reduced tumor growth in preclinical models. These data demonstrate that PVRIG is a promising target for the treatment of cancer and provide the rationale for COM701 as a potential cancer immunotherapy.
Association of CMB305 or LV305-induced and baseline anti-NY-ESO-1 immunity with survival in recurrent cancer patients.
Authors: Pollack Seth , Lu Hailing , Somaiah Neeta , Chawla Sant P. , Morris John Charles , Do Khanh Tu , Kim Joseph W. , Block Matthew Stephen , Vignali Marissa , Rytlewski Julie , Yusko Erik , Hsu Frank J. , Bohac Gerry C. , Gnjatic Sacha , Ter Meulen Jan
Published: September 2018

3090

Background: The correlation of immune response (IR) and clinical benefit in patients (pts) who receive active immunotherapy remains controversial. CMB305 is an active immunotherapy designed to generate and expand anti-NY-ESO-1 T cells, consisting of LV305 (a DC targeting lentiviral vector encoding NY-ESO-1) and a boost (NY-ESO-1 recombinant protein plus GLA-SE, a TLR-4 agonist). Phase 1 studies of LV305 and CMB305 evaluated the IR and survival of pts with NY-ESO-1 positive tumors. Methods: 62 pts with recurrent NY-ESO-1 expressing (by IHC) solid tumors were enrolled in 2 Phase 1 trials (31 pts each: 43 sarcomas, 12 ovarian, 4 melanomas, and 3 NSCLC). Peripheral blood was assessed pre and post therapy for anti-NY-ESO-1 T cell responses (IFNγ ELISPOT) and antibodies (Ab) (ELISA) (n = 62), TCR-β CDR3 repertoire and conserved (public) TCR (n = 28), and antigen spreading (ELISA, ELISPOT) (n = 23). Relationship between progression-free survival (PFS), overall survival (OS) and up to 15 biomarkers were analyzed by the Kaplan-Meier method. Results: Preexisting anti-NY-ESO-1 T cells and Ab were identified in 34% and 40% of pts. LV305 and CMB305 induced (de novo or increased) anti-NY-ESO-1 T-cells in 51% and 65% pts, and anti-NY-ESO-1 Ab responses in 13% and 68% pts, respectively. LV305 and CMB305 induced antigen spreading in 17% and 36% pts. TCR clonality increased after CMB305 as compared to LV305. The TCRβ-CDR3 amino acid sequences of three NY-ESO-1 specific TCR clones in a patient with a > 2-year response were fully conserved in 20/28 patients. Biomarkers showing the strongest association with OS and PFS were pre-existing anti-NY-ESO-1 T-cell response and Ab, integrated IR (T cells and antibodies), and NY-ESO-1 expression level. Presence of public TCRs was associated with longer survival, particularly in pts with high ( > 50%) NY-ESO-1 expression. Conclusions: While LV305 and CMB305 are both immunogenic, CMB305 resulted in a stronger and broader integrated IR, including antigen spreading. The three identified survival variables, preexisting and treatment-induced NY-ESO-1 IR and the presence of public TCRs, warrant validation in randomized studies of CMB305.
Impact of consensus molecular subtyping (CMS) on overall survival (OS) and progression free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance).
Authors: Lenz Heinz-Josef , Ou Fang-Shu , Venook Alan P. , Hochster Howard S. , Niedzwiecki Donna , Goldberg Richard M. , Mayer Robert J. , Bertagnolli Monica M. , Blanke Charles David , Zemla Tyler , Qu Xueping , Innocenti Federico , Kabbarah Omar
Published: September 2018

3511

Background: CALGB 80405 was a randomized Ph3 trial showing no OS or PFS difference in mCRC pts treated with Bevacizumab (BV) or Cetuximab (Cet) in the first line. A Nanostring platform was used to determine the CMS classification of 392 KRAS wt (codon 12 and 13) primary tumors and correlated it with OS and PFS in patients enrolled in 80405. Methods: CMS for 392 of 431tumors were defined using a custom CRC Nanostring panel (39 CMS classification not possible). Stratified Cox proportional hazard model was used to evaluate the effect of CMS classification stratified by prior radiation, prior chemotherapy, adjusting for age, sex, race, primary in place, liver met only, and sidedness. Results: We found CMS1 (14%), CMS2 (47%), CMS3 (2%), CMS4 (29%), NonConsensus (8%). Results are shown in Table 1. Patients with CMS1 who received BV had significantly longer OS than those who received Cet (HR 0.47, 95% CI [0.24, 0.92]). Patients with CMS2 who received BV tended to have shorter OS than those who received Cet (HR 1.41, CI [0.95, 2.08]). Conclusions: Our data suggest that CMS is associated with OS and PFS in first line therapy in mCRC patients. Preliminary data suggest that certain CMS may be associated with efficacy of Bev and Cet based chemotherapy. CMS classification should be explored as a stratification factor in future trials. Support: U10CA180821, U10CA180830, U10CA180882 Clinical trial information: NCT00265850. [Table: see text]