Background

BO-112 is a synthetic dsRNA formulated with a cationic carrier, polyethylenimine, which prevents its degradation by nucleases. In melanoma (MEL) mouse models, systemic administration of BO-112 activates MDA-5 and NOXA, leading to anti-tumoral activity connected to a sustained and extended expression of interferon (IFN) response genes. IT BO-112 delivery demonstrated in transplanted mouse models a safer and enhanced local and systemic antitumor effects. Final toxicity and biological profile of the first in human clinical trial that explores IT BO112 as an immune-modulatory treatment is presented (NCT02828098).

Methods

Patients (pts) with solid malignant tumors and metastases ≥1 cm accessible to IT injection were treated in 3 cohorts (C) in a 3 + 3 phase I design: C1: single IT BO-112 dose of 0.6 mg; C2: 1mg IT BO112 qw x 2-3 doses. C3: 0.6 mg IT BO112 qw x 2-3 doses. Pre & post treatment biopsies from the injected lesion were obtained, analysing necrosis, apoptosis, immune infiltrate and (first time reported for this trial) IFN-gamma mRNA expression (nanostring). PKs, cytokines and circulating immune cells (CICs) were studied in pre and post BO-112 blood samples.

Results

16 pts (12 more than the first report in ASCO 2017) were treated: 5 MEL, 3 sarcoma, 2 breast, 1 colorrectal, 1 neuroendocrine, 1 ovarian, 1 head & neck, 1 mesothelioma and 1 cystic adenoid. 50% pts had related AEs, being 94% G1-2 and 6% G3-4 (thrombocytopenia in 2 pts in C1 and C2, both considered DLT and recovered) BO112 was not detected in blood in any pts. Table summarizes the biological parameters that increase after BO112 treatment in tumor/blood samples.Table:

LBA20

Conclusions

BO112 demonstrated a manageable safety profile. Its biological activity is consistent with both a direct antitumor effect and with intratumoral and systemic immunity activation, driven by IFN-gamma pathway. 1mg qw x 2-3 doses in combination with anti-PD-1 is the chosen regimen for an expansion cohort in pts refractory to anti-PD-1 therapy.

Clinical trial identification

NCT02828098 Release date: June 23, 2016

Legal entity responsible for the study

Bioncotech Theraputics

Funding

Bioncotech Theraputics

Disclosure

I. Marquez Rodas: Advisory role form BMS, MSD, Novartis, Roche, Pierre Fabre, Amgen and Bioncotech S. Lopez-Tarruella Cobo: Advisory Role (Novartis, Pfizer, Celgene) y Honoraria/lecturer (Novartis, Pfizer, AZ, Celgene, Roche) L. Planelles, M. Quintero: Bioncotech (employment) S. Martin Algarra: Advisory role for BMS, MSD, Novartis, Roche, Amgen I. Melero: Advisory role/consulting AstraZeneca; Bristol-Myers Squibb; Pfizer; Roche/Genentech All other authors have declared no conflicts of interest.

Background

Malignant Pleural Mesothelioma (MPM) remains a major challenge with limited therapeutic options. Disease is frequently confined to the pleura, distant metastases are uncommon and intrapleural treatment is therefore appealing. HSV1716 is a 34.5null oncolytic herpes simplex virus which, in pre-clinical studies, demonstrates cancer cell-specific HSV1716 infection and oncolysis and an anti-tumor immune response. We assessed the safety and potential for efficacy of intrapleural HSV1716 in patients with inoperable MPM.

Methods

We performed an open label, dose escalation, phase I/IIa trial of intra-pleural HSV1716. Patients with a histological diagnosis of MPM and indwelling pleural catheter (IPC) were eligible if they had performance status ≤ 2 and adequate hematologic, renal and liver function. Patients received 1x10⁷pfu HSV1716 through their IPC on 1, 2 or 4 occasions a week apart, in 3 separate cohorts. The primary objective was to determine the safety and tolerability of intra-pleural HSV1716. The secondary objectives were to assess HSV1716 replication and patient immune responses in pleural fluid and blood. An exploratory objective was to assess tumour response by CT, using modified RECIST criteria.

Results

Twelve patients were treated, 3 received 1 dose of intrapleural HSV1716, 3 received 2 doses and 6 received 4 doses. HSV1716 was well-tolerated with no HSV1716-related SAE and 17 HSV1716-related transient Grade 1-2 AEs. Evidence of HSV1716 replication (n = 9) and pleural Th1 cytokine responses (n = 8) were observed. Novel anti-tumor IgG responses were detected post treatment and their antigen targets identified by protein array. CT analysis on day 57 indicated 6 patients with stable and 6 patients with progressive disease. Median survival from treatment was 15mths for all patients and 18mths in patients with evidence of a Th1 immune response (n = 8).

Conclusions

The study demonstrated an acceptable safety profile of intra-pleural HSV1716 with evidence of viral replication and anti-tumour immunogenicity. This supports further studies in MPM, possibly involving combination with immune checkpoint inhibitors.

Clinical trial identification

NCT01721018

Legal entity responsible for the study

Virttu Biologics Ltd

Funding

Virttu Biologics Ltd

Disclosure

S. Danson: Advisory role for Incathera Research funding from Lilly, GSK, Bristol-Myers Squibb, Astellas, Incyte, Novartis, Boehringer. P. Woll: Consulting/Advisory role to Lilly, Theradex. Research funding from AstraZeneca, Pfizer, Virttu. P. Fisher: Consulting/Advisory Role to Diaceutics. Research Funding from Pierre Fabre, Pfizer, Bristol-Myers Squibb. J. Roman, K. Simpson, R. Spavin, K. Learmonth, J. Conner: Employee of Virttu Biologics. All other authors have declared no conflicts of interest.

Background

CEA-CD3 TCB (RG7802, RO6958688) is a novel T-cell bispecific antibody targeting CEA on tumor cells and CD3 on T cells. An ongoing phase Ib study (NCT02650713) is exploring the safety, tolerability and efficacy of CEA-CD3 TCB in combination with atezolizumab. We report preliminary results of FDG-PET imaging as an early pharmacodynamic marker for this novel cancer immunotherapy combination in MSS mCRC patients.

Methods

In this study, CEA-CD3 TCB is given QW in combination with atezolizumab 1200 mg Q3W in patients with CEA-expressing solid tumors. As of March 3, 2017, a total of 35 MSS mCRC patients have been treated with CEA-CD3 TCB doses of 5-160 mg; 15 patients were evaluable for PET image analysis. On-treatment FDG-PET scans were performed at week 4 and compared with baseline. On-treatment changes in SUV_max, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were analyzed in up to 10 measurable lesions per patient, identified at baseline by an independent reviewer. The exploratory statistical analyses used semiparametric Gaussian regression models and Cox PH landmark analyses (for progression-free survival [PFS]).

Results

Early changes in FDG-PET parameters showed a dose-response relationship (MTV: P = 0.0022; TLG: P = 0.0054; SUV_max: P = 0.0081); notably all patients receiving doses ≥ 80 mg (n = 7) showed decreases in SUV_max, TLG and MTV at week 4. Furthermore, week 4 reductions in FDG uptake (MTV: P < 0.001; TLG: P < 0.001; SUV_max: P = 0.0061) correlated with later tumor shrinkage (best change from baseline per RECIST v1.1). Reduction in MTV and TLG, but not SUV_max, correlated with decreases in soluble CEA levels measured at week 6 (MTV: P = 0.013; TLG: P = 0.034; SUV_max: P = 0.54) and longer PFS (MTV: P = 0.013; TLG: P = 0.052; SUV_max: P = 0.85).

Conclusions

In MSS mCRC patients, changes in MTV, TLG and SUV_max correlated with dose and tumor shrinkage. Decreases in 2 FDG parameters (MTV and TLG) correlated with a reduction in soluble CEA levels. Early on-treatment changes in FDG-PET can serve as a pharmacodynamic biomarker related to treatment efficacy.

Clinical trial identification

NCT02650713

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd.

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

F. Sandoval, D. Sabanes Bove, S. Bouseida, V. Karanikas, A. Keelara: Roche employee. J. Saro: Employee of Roche and stock holder of Roche. T. Nayak: Roche stock.

Background

Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a class of antitumor agents that exert their cytotoxic effects by inhibiting PARP activity. Some PARPis are capable of trapping PARP proteins on DNA further augmenting cell death. BGB-290 is a potent and selective PARP1/2 inhibitor with strong PARP-trapping and antitumor activity in both in vitro and in vivo preclinical tumor models harboring BRCA gene mutations or other homologous recombination defects.

Methods

This two-staged study (NCT02361723) consists of a Phase 1A dose-escalation/dose-finding component to establish the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of BGB-290 in patients with solid tumors and a two-part Phase 2 component that includes expansion in targeted indications (Part A) and the effect of food on the BGB-290 pharmacokinetic (PK) profile (Part B).

Results

As of 1 May 2017, Phase 1A had completed enrollment (n = 45); 3 patients remain on treatment. Objective responses were observed across the dose range (2.5–120 mg BID). Of the 23 evaluable patients with gynecological cancer, 10 (43%) achieved an objective response per RECIST 1.1 (n = 3 complete; n = 7 partial). More patients with germline BRCA 1/2 mutated ovarian cancer achieved an objective response (n = 7/12, 58%) than patients not carrying the mutation (n = 2/8, 25%). Drug-related adverse events (AEs) reported in ≥ 10% of patients were nausea, fatigue, anemia, vomiting, diarrhea, anorexia and neutropenia. Anemia and neutropenia were the most common drug-related Grade 3 AEs; no Grade 4 drug-related AEs were reported. Three BGB-290-related serious AEs were reported (anemia, n = 2; nausea, n = 1). Four deaths were associated with an AE; however, none were considered drug-related. The BGB-290 RP2D was determined as 60 mg BID and is being evaluated in Phase 2 to determine antitumor activity and food effects. Dose escalation to determine MTD with QD dosing is ongoing.

Conclusions

BGB-290 has demonstrated a favorable safety profile and promising preliminary antitumor activity in phase 1A; phase 2 is ongoing evaluating in patients with ovarian, breast, prostate, gastric and small cell lung cancer.

Clinical trial identification

NCT02361723, January 29, 2015

Legal entity responsible for the study

Beigene Ltd.

Funding

Beigene Ltd.

Disclosure

T. Meniawy: Non-financial support and other from Beigene during the conduct of the study. T. Tang, R. Wei, M. Li, V. Paton: Employee of BeiGene. All other authors have declared no conflicts of interest.

Background

Aberrant PI3K/Akt/mTOR (PAM) pathway signaling is observed in various tumors and confers resistance to standard therapies. M2698 is an oral, brain penetrant, potent and selective p70S6K/Akt1/3 inhibitor that can block signaling from Akt feedback loop activation, a possible tumor escape mechanism

Methods

Patients (pts) with advanced cancer were given oral M2698 daily (PO 15–380 mg) in 21-day (d) cycles in a 3 + 3 dose escalation [DE] design. Response was assessed every 2 cycles. An expansion phase in pts with PAM pathway tumor alterations is ongoing

Results

Overall, 50 pts received M2698 monotherapy (DE, n = 40; expansion, n = 10); DE data presented only (cut-off 10/27/16). Treated pts had a median age of 56 years. (14 men, 26 women). Tumor types included breast (n = 7), colon (n = 4), lung (n = 4) and other (n = 25). In the DE phase, 35/40 pts were evaluable. Two pts had a dose limiting toxicity (DLT; 60mg and 160mg) and drug-related Grade ≥3 adverse events (AEs) occurred in 6/40 (15%) of pts. AEs leading to dose reductions occurred in 1 pt at < 320 mg/d and in 3 pts ≥320 mg/d. Of the 32 DE pts (without DLT) who completed treatment by the data cut-off, 6 pts (19%) remained on treatment (Rx) for ≥ 180 days (min, max range 21 to 504 days) [Table]. Exposure of M2698 increased dose proportionally and ³80% phospho-S6 inhibition in tumor was achieved in 2/7 paired biopsies from pts treated with doses ³110 mg/d. Expansion phase dose was 240 mg/d PO. Tissue molecular analysis and liquid biopsies were performed. Analysis is ongoing.Table:

370PD

Conclusions

M2698 was well tolerated and provided stable disease over a wide range of doses.

Clinical trial identification

NCT01971515

Legal entity responsible for the study

Merck KGaA, Darmstadt, Germany

Funding

Merck KGaA, Darmstadt, Germany

Disclosure

G. Lopes, R. Kurzrock: Research funding from Merck. A. Victor: Merck employee. J. Shaw, R. Kaleta: EMD Serono employee. All other authors have declared no conflicts of interest.

Background

RAS-RAF-MEK and PI3K-AKT-mTOR are two major pathways involved in tumor cell signaling and growth. Components of these pathways are frequently mutated in a broad range of tumors. ASN003 is a highly selective and potent (low nM IC₅₀) inhibitor of BRAF and PI3K-α and -d (low affinity for PI3K-b). ASN003 shows strong antitumor activity in tumor models harboring BRAF and PIK3CA or PTEN mutations, and also in PDX models that are resistant to selective BRAF and MEK inhibitors.

Methods

Oral ASN003 once daily is being evaluated for safety/tolerability and preliminary efficacy in eligible patients with advanced solid tumors using an accelerated dose titration design (Part A) and enrolling cohorts of melanoma, CRC and NSCLC patients with a BRAF, PIK3CA or PTEN mutation at MTD (Part B). Eligibility criteria include HbA1c ≤ ULN or fasting glucose <140 mg/dL. Pharmacokinetic (PK) profile and the pharmacodynamic (PD) effects of ASN003 on tumor tissue biomarkers such as pERK and pS6 are investigated in both parts of the study.

Results

Patient accrual is ongoing. To date, seven eligible patients are enrolled in dose levels ranging from 10 – 120 mg QD. ASN003 has been well tolerated. Treatment-related adverse events (TRAEs) were mild (G1) to moderate (G2). TRAEs include diarrhea (G2) (n = 1), nausea/vomiting (G1) and dry mouth/lips/skin (G1). Transient G1 elevation of glucose and insulin c-peptide levels has been noted in 1 pt. No G3/4 AEs have been observed to date. The PK profile showed excellent, systemic exposure at steady state at all doses (C_max up to 930 ng/mL, AUC_0-T up to 18998 ng.h/mL at 80 mg QD) and a half-life of > 12 hour. Dose escalation is ongoing.

Conclusions

ASN003 is a novel small molecule, with uniquely selective and potent inhibition of BRAF, PI3-α and -d kinases. To date, ASN003 was well tolerated at doses up to 120 mg QD and achieved good systemic exposure. Updated and detailed clinical safety/efficacy and PK/PD results will be presented.

Clinical trial identification

NCT02961283

Legal entity responsible for the study

Asana BioSciences

Funding

Asana BioSciences

Disclosure

S. Reddy, N. Rao, L. Denis: Employee and Stock Ownership Asana BioSciences. A. Tolcher, K.T. Flaherty: Member of Scientific Advisory Board Asana BioSciences. All other authors have declared no conflicts of interest.

Background

Dysregulation of the FGF/FGFR signaling pathway has been associated with many developmental disorders and varieties of cancers. TAS-120 is an oral, highly selective covalent FGFR inhibitor with potent antitumor activity in vitro and in vivo models with FGFR pathway aberration.

Methods

This FIH study consists of dose escalation phase (DE) and expansion phase (EX). The objectives of this study are to determine the maximum tolerated dose (MTD)/recommended dose (RD) and to investigate the safety, pharmacokinetics, pharmacodynamics, and efficacy. In DE, the first three cohorts were evaluated by a single patient then a 3 + 3 design is used which is currently ongoing. Pts with FGFR abnormalities can be enrolled to EX during the evaluation of DE with dose lower than maximum administered dose under evaluation. TAS-120 was administered orally three times weekly (Monday-Wednesday-Friday) in a 21day cycle.

Results

As of 3 Apr 2017, 36 pts (34% FGFR with genetic abnormalities) were enrolled (DE; 26 pts, EX; 10 pts). Tumor types enrolled were bladder cancer (n = 8), colorectal cancer (n = 7), biliary tract cancer (n = 4), gastric, esophageal and pancreas cancer (n = 3 each), and others (n = 8). Pts were treated in 8 dose cohorts of 8 -160 mg. MTD has not been reached. The most common drug-related AEs (all AEs ≥10%) were hyperphosphatemia (79%), and anorexia (12%). Grade ≥3 hyperphosphatemia has never been observed. Hyperphosphatemia was managed with dose interruption or reduction in addition of phosphate binders. Drug-related SAE has not occurred. TAS-120 exposure increased with dosage. Mean C_max and AUC_0-48 at 160 mg were 1,192 ng/mL and 9,972 ng*h/mL, respectively, with a mean T_max of 2.67 hrs and apparent T_1/2 of 6.06 hrs. Two pts showed the clinical response, one of them was gastric cancer with FGFR2 amplification at 80 mg, and the other was esophageal cancer (FGFR status is under evaluation) at 120 mg. Moreover, two biliary tract cancer with FGFR2 fusion at 56 mg, and one bladder cancer at 36 mg (FGFR status is unknown) had stable disease > 24 weeks.

Conclusions

TAS-120 was well-tolerated, and the safety profile was confirmed up to 120 mg. The ongoing DE and EX are still under evaluation and RD will be determined.

Clinical trial identification

Clinical trial information: JapicCTI-142552

Legal entity responsible for the study

TAIHO Pharmaceutical co., LTD.

Funding

TAIHO Pharmaceutical co., LTD.

Disclosure

Y. Kuboki: Honoraria: Taiho Pharmaceutical, Bayer. N. Matsubara: Advisory Board: Janssen, AstraZeneca. Corporate-sponsored research: Janssen, Bayer. Honoraria: Taiho Pharmaceutical. Speakers’ Bureau: Janssen, AstraZeneca, Sanofi. H. Bando: Corporate-sponsored research: AstraZeneca, Sysmex, FALCO Biosystems. Speakers’ Bureau: Taiho Pharmaceutical, Lilly, Takeda, Merck Serono, Chugai, Yakult. K. Shitara: Advisory Board: Bayer, Chugai, Lilly, Takeda. Corporate-sponsored research: Bayer, Chugai, Dainippon Sumitomo, Lilly, MSD, Sanofi, Daiichi Sankyo, Taiho, Yakult. Honoraria: Bayer, Chugai, Bristol-Myers Squibb, Novartis, Takeda. K. Yoh: Corporate-sponsored research: AstraZeneca, Lilly, Taiho Pharmaceutical, Pfizer. Honoraria: AstraZeneca, Chugai, Boehringer Ingelheim, Lilly, Bristol-Myers Squibb, Taiho Pharmaceutical, Ono Pharmaceutical. T. Kojima: Corporate-sponsored research: AstraZeneca, Ono Pharmaceutical, Shionogi, MSD, Merck Serono, Taiho Pharmaceutical. Speakers’ Bureau: Chugai. I. Ohno: Advisory Board: Merck Serono. H. Takahashi: Corporate-sponsored research: Bayer, Bristol-Myers Squibb. Honoraria: Taiho Pharmaceutical. S. Kondo: Corporate-sponsored research: AstraZeneca, Lilly, Pfizer, ASLAN, Merck Serono. H. Hirai: Employee: Taiho Pharmaceutical. C. Morizane: Advisory Board: AstraZeneca, Yakult, Novartis, Taiho. Corporate-sponsored research: GlaxoSmithKline, Pfizer, Nobelpharma, Eisai, Yakult, Ono, Taiho. Honoraria: Pfizer, Novartis, Yakult, Lilly, Nobelpharma, Fujifilm. T. Doi: Advisory Board: Lilly, Chugai, Kyowa Hakko Kirin, Novartis, MSD, Daiichi Sankyo, Amgen. Corporate-sponsored research: Taiho, Merck, Astellas, Janssen, Takeda, Pfizer, Lilly, Sumitomo Group, Bayer, Chugai, Kyowa Hakko Kirin, Boehringer, Novartis, MSD, Daiichi Sankyo, Celgene. All other authors have declared no conflicts of interest.

Background

E7046 is a selective small molecule antagonist of the prostaglandin E₂ receptor-type-4 that inhibits the differentiation of monocytic myeloid lineage cells towards a pro-tumorigenic phenotype in the TME. This is a first-in-human study of single-agent E7046.

Methods

Key eligibility criteria: patients (pts) ≥18 years with selected advanced cancers with high levels of myeloid infiltrate. The dose-escalation phase consisted of 6-pt cohorts of 125, 250, 500, and 750 mg (once-daily, oral, 21-day cycle) doses of E7046. Primary objectives were safety/tolerability, maximum tolerated dose (MTD) and/or RP2D. Secondary objectives included PK and initial anti-tumor activity; exploratory objectives included PD assessments on immune cells in tumor infiltrate and in peripheral blood and metabolic response by ¹⁸FDG-PET.

Results

30 pts received E7046 (median age 58 yrs [24-78]; 2-7 lines of prior therapy). Most common tumor types were colorectal cancer (40%), pancreatic cancer (20%), and SCCHN (13%). No DLTs were observed and the MTD was not reached. The most frequent drug-related adverse events (AEs) were diarrhea (20%), decreased appetite, fatigue and nausea (13% each). Drug-related AEs of Gr 3/4 occurred in 4 pts (diarrhea, anaphylactic reaction, hypersensitivity, hyperuricemia, rash, generalized rash). 2 pts had drug-related serious AEs (rash, allergic reaction, fever in 1 pt; hyperuricemia, acute renal failure [Gr 2] in 1 pt). 3 pts discontinued treatment due to AEs (bowel obstruction, allergic reaction, abdominal pain). There were no drug-related deaths. E7046 exposure was dose proportional up to 500 mg with no incremental increase in exposure at 750 mg. E7046 was extensively metabolized, elimination half-life was ∼12hr and accumulation on multiple dosing was ∼2-fold. 2 pts are ongoing and preliminary efficacy showed no objective responses, 4 pts with durable SD or clinically stable (>4 mo) and 4 pts with ¹⁸FDG-PET metabolic responses.

Conclusions

Single-agent E7046 was tolerated with no MTD reached in heavily pretreated pts with myeloid-rich tumors. PD analysis of immune cell modulation to help determine the RP2D will be presented at the meeting.

Clinical trial identification

NCT02540291

Legal entity responsible for the study

Eisai Inc.

Funding

Eisai Inc.

Disclosure

D.S. Hong: Research/Grant Funding: Bayer, Lilly, Genentech, LOXO, Pfizer, Amgen, Mirati, Ignyta, Merck, Daichi-Sanko, Eisai. Travel/Accommodations: MiRNA, LOXO. Consulting/Advisory: Bayer, Baxter, Guidepoint Global. Other interests: Oncoreseponse (founder). L. Reyderman, M. Ren, T. Binder, C.E. Ooi, S. Dayal, O. Ataman: Employee of Eisai Ltd. A. Marabelle: Clinical trial funding from Eisai. Consulting fees from Eisai and Roche. Funding for anti-CSF1R clinical trial from Roche. All other authors have declared no conflicts of interest.

Background

KPT-9274 is an oral, small molecule modulator of PAK4 (p21 activated kinase) and NAMPT (nicotinamide phosphoribosyltransferase). PAK4 is a major player in cell morphology and WNT/β-catenin signaling. NAMPT is the rate-limiting enzyme in NAD biosynthesis. Co-inhibition of these targets leads to synergistic anti-tumor effects through energy depletion, inhibition of DNA repair, cell cycle arrest, and ultimately apoptosis. Cells can utilize niacin to make NAD through an alternative pathway using NAPRT1. NAPRT1 is often absent in tumors making it a potential response biomarker. KPT-9274 demonstrates potent anti-tumor activity pre-clinically and in patient dogs with cancer.

Methods

This dose escalation study evaluates KPT-9274 as a single agent and co-dosed with niacin. KPT-9274 is given QoDx3/week (28-day cycle) at a starting dose of 10 mg. The objectives are to evaluate safety and tolerability of KPT-9274, dose-limiting toxicities (DLT), maximum tolerated dose (MTD), recommended phase 2 dose, early antitumor activities, pharmacokinetic (PK) and pharmacodynamic properties.

Results

As of 02-Mar-17, 14 patients (pts: 9M/5F; median age 61) with advanced solid tumors were enrolled in 4 cohorts (10 – 40 mg). One DLT (G4 anemia) at 40 mg was reported. MTD is not yet reached. Drug-related adverse events (AEs) include G2-4 anemia (6 pts, 43%) and G3 fatigue (1 pt, 7%). The most common G2 AEs are arthralgia and myalgia (3 pts; 21% each) and influenza-like illness (2 pts; 14%). Stable disease (SD) was seen in 29% of the 14 pts. Preliminary PK analysis suggests plasma exposure was dose proportional on C1D1 increasing 4 to 5-fold by C1D24. On C1D24, the mean C_max and AUC_0-t observed in 20 – 30 mg cohorts were 319 – 1,573 ng/mL and 10,456 – 59,152 ng*hr/mL, respectively. Preliminary data indicate that treatment of KPT-9274 reduces NAD levels vs. baseline in circulating leukocytes and tumor biopsies. Analyses to correlate NAPRT1 status with response is ongoing (2 of 4 SD pts are NAPRT1-).

Conclusions

Oral KPT-9274 is tolerated in pts with advanced solid malignancies. Anemia, arthralgias and myalgias are common AEs with one DLT (G4 anemia). PK is generally proportional and predictable.

Clinical trial identification

NCT02702492

Legal entity responsible for the study

Karyopharm Therapeutics Inc

Funding

Karyopharm Therapeutics Inc

Disclosure

W. Senapedis, S. Shacham, J. Meade, J. Ellis, E. Baloglu: Employee and a stock holder of Karyopharm Therapeutics. M. Kauffman: Employee, stock holder and member of board of directors at Karyopharm Therapeutics. All other authors have declared no conflicts of interest.

Background

Checkpoint kinase 1 (Chk1) inhibition following chemotherapy overrides cell cycle arrest and induces mitotic catastrophe and cell death. GDC-0575 is a highly-selective oral small-molecule Chk1 inhibitor that results in tumor shrinkage and growth delay in xenograft models.

Methods

This Phase I trial enrolled pts with refractory solid tumors and ECOG 0-1 status. Patients received IV gem 1000 mg/m² followed ∼24 hours later by GDC-0575 (15-60 mg) PO, or IV gem 500 mg/m² followed ∼24 hours later by GDC-0575 (45-105 mg) PO, weekly for 2 of 3-week cycles. TP53 was evaluated in archival tumor tissue by gene sequencing. Safety, pharmacokinetics (PK), pharmacodynamics, and tumor response by RECIST v1.1 were investigated.

Results

Of 81 pts treated, 73% were female, the median age was 56 years (range 27-75), and 48% were ECOG PS 0. The most common tumor types were breast (46%), and soft tissue sarcoma and NSCLC (both 7%). Dose escalation was halted at GDC-0575 60 mg and 105 mg with gem 1000 mg/m² and gem 500 mg/m², respectively, as pts experienced Grade 4 thrombocytopenia and Grade 3-4 febrile neutropenia as dose-limiting toxicities. The most frequent adverse events (all grades) related to GDC-0575 and/or gem were neutropenia (80%), anemia (56%), fatigue (47%), nausea (46%), and thrombocytopenia (40%). Maximum concentrations of GDC-0575 were achieved within 2 hours of dosing, and its half-life was ∼23 hours. No PK drug-drug interaction was observed between GDC-0575 and gem. Among pts treated with GDC-0575 and gem 500 mg/m², there were 4 cPRs (2x sarcoma, NSCLC, TNBC) and 3 SDs (TNBC, NSCLC, SCLC) for ≥ 6 months. Exome sequencing data from tumor samples obtained at progression did not reveal mutations in Chk1 but identified mutations in genes known to regulate apoptosis.

Conclusions

The Chk1 inhibitor GDC-0575 can be safely combined with a standard or modified dose and schedule of gem. Hematological toxicities were frequent but manageable. Preliminary anti-tumor activity was observed in patients with a variety of refractory solid tumors treated with GDC-0575 in combination with gem 500 mg/m².

Clinical trial identification

NCT01564251

Legal entity responsible for the study

Genentech, Inc.

Funding

Genentech, Inc.

Disclosure

G. Shapiro: Advisory boards for Pfizer, Lilly, G1 Therapeutics, Roche and Vertex Pharmaceuticals. Research funding from Pfizer and Lilly. K.N. Moore: Advisory boards for Advaxis, AstraZeneca, Clovis, Immunogen, Genentech/Roche, Tesaro and VBL therapeutics. P. Lorusso: AstraZeneca, Roche Genentech, AbbVie, Bayer, Boerhinger Ingelheim, Alexion, Omniox. E. Blackwood, S. Mahrus, X. Lu, M. Tagen, J. Schutzman, J. Lauchle: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd. J-C. Soria: Consultancy fees from AstraZeneca, Astex, Covagen, Clovis, GSK, Gammamabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, Pierre Fabre, Roche-Genentech, Sanofi, Servier, Takeda. All other authors have declared no conflicts of interest.