bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I study of LY573636-sodium, an acylsulfonamide anti-cancer compound with a novel mechanism of action, administered as 2-hour IV infusion in patients with advanced solid tumors
Authors: Ilaria R. L. , Simon G. R. , Sovak M. , Burton M. K. , Cleverly A. L. , Sykes A. K. , De Alwis D. P. , Wagner M. M. , Spriggs D. R.
Published: March 2020

2515

Background: LY573636 -sodium (hereafter referred to as LY573636 ) is a novel anti-cancer compound that induces apoptosis by a mitochondrial-mediated mechanism. Methods: A phase I study was conducted to determine the maximum tolerated dose (MTD) and pharmacokinetic (PK) profile of LY573636 administered as an intravenous infusion over 2 hours every 21 days. Results: 53 patients (pts) were enrolled on study, 16 males, 37 females, with a median age of 58 (range: 18–83). LY573636 was dose-escalated using a flat dosing paradigm in the first 34 patients (range 100 mg to 2400 mg). PK analysis of this cohort revealed that LY573636 had a low total plasma clearance (CL = 0.02L/hr) and terminal elimination half-life of approximately 340 hours due to high-albumin binding (∼99%). The dose limiting toxicity (DLT) for the flat dose escalation was bone marrow (BM) suppression, which included CTC (ver2) grade 3/4 thrombocytopenia/neutropenia. In some patients, significant BM suppression occurred in cycle 2 and later, attributed to the accumulation of albumin-bound drug with repeated flat dosing. Based on these findings, the dose-finding strategy was modified to an idealized dosing paradigm which calculated LY573636 doses based on pt lean body weight, and used a loading/maintenance dose regimen to achieve a specific Cmax target value. All 3 pts in the first 400 μg/mL Cmax cohort completed at least 2 cycles and no DLTs were reported. Of the 16 pts enrolled to the 420 μg/mL targeted dose group: 1 pt reported a DLT, a transient grade 3 elevation of ALT/AST which did not recur in subsequent cycles; 8/16 pts received 4 or more cycles prior to disease progression and 2 remain on treatment. Overall, 23/53 pts had stable disease (SD) after 2 or more cycles. Seven pts received >8 cycles (SD > 6 mos), including heavily pre-treated pts with ovarian cancer, non-small cell lung cancer, soft tissue sarcoma, and thymoma. Conclusions: LY573636 is a novel anti-cancer compound with a unique mechanism of action. The most common DLT was BM suppression. The individualized, target Cmax dose of 420 μg/mL has been taken forward into phase II clinical trials.

No significant financial relationships to disclose.
A phase I trial of lomeguatrib and irinotecan in metastatic colorectal cancer
Authors: Sabharwal A. , Corrie P. , Seebaran A. , Anderson D. , Carmichael J. , Mortimer P. , Margison G. P. , Watson A. , Middleton M. R.
Published: March 2020

2535

Background: The DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) contributes to cellular resistance to irinotecan (IR) and its metabolite SN-38. In human cancer cell lines MGMT expression correlates with SN-38 sensitivity, inactivation of MGMT enhances cell killing and increasing MGMT expression by transfection increases resistance to IR. This study evaluated the safety, tolerability and pharmacokinetics (PK) and pharmacodynamic (PD) effects of lomeguatrib (LM), an MGMT inactivator, in combination with IR. Methods: Patients with stage 4 colorectal cancer, performance status 0–2 and adequate bone marrow and biochemical function took part in the trial, which followed a standard 3 patient cohort dose escalation design. LM was given daily PO for 5 days, with IR by IVI on day 4 of each 21 day cycle. Starting doses were 10 mg/day LM and 350 mg/m2 IR. Tumor response to treatment was measured by RECIST criteria. Blood was taken for PK & PD measurements in cycle 1. Results: 24 patients (14M/10F; median age 62) were enrolled. The first dose level was not tolerated, with 2 of 3 patients experiencing dose limiting haematological toxicity. The IR dose was decreased to 250 mg/m2 for subsequent cohorts, and the LM dose escalated from 10 to 80 mg/day. With LM 80 mg/day a final 6 patient cohort received 300 mg/m2 IR, establishing this as the maximum tolerated dose. Non-hematological toxicity matched that of single agent IR. No partial responses have been seen amongst 22 evaluable patients. 10 patients had prolonged disease stabilisation, completing all 6 treatment cycles, with another 3 patients still on treatment. There was no PK interaction between the drugs. Conclusion: LM and IR is well tolerated, requiring a modest reduction in the single agent dose of IR. Clinical activity, in this pre-treated population, is modest. PD data on MGMT levels and DNA-topoisomerase 1 complex formation in peripheral blood mononuclear cells, measured by bioassay and RIA respectively, will be presented.

No significant financial relationships to disclose.
Prediction of response to chemotherapy using sequential F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) in patients with metastatic colorectal cancer
Authors: Kim J. , Choi S. , Yi H. , Lim J. , Lee M. , Hyun I. , Kim C.
Published: March 2020

2536

Background: Clinical response is determined after 2 or 3 cycles of chemotherapy by changes in tumor size as assessed by conventional imaging procedures such as computed tomography (CT). The aim of this study was to evaluate the use of sequential F-18 FDG PET to predict response to standardized chemotherapy for metastatic colorectal cancer (mCRC). Methods: Clinical response, as assessed by RECIST criteria, served as the reference. Investigators were free to choose chemotherapy regimen. F-18 FDG PET images after every second cycles of chemotherapy were analyzed semiquantitatively for each metastatic lesion using standardized uptake values (SUVs) normalized to patients’ blood glucose levels. PET responses were prospectively assessed as either complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), or progressive metabolic disease (PMD). In addition, sum of SUV of all metastatic lesions (sSUV) and a maximal SUV (mSUV) were recorded each PET-CT scan. Results: Twenty-four patients underwent 73 PET-CT scans since March 2005. The response to chemotherapy included CR in 1 (4.2%), PR in 10 (42%) by RECIST criteria. Median duration of follow- up was 8.3 months (range, 1.7 - 16.2) and median progression free survival (PFS) time was 6.4 months. At the baseline evaluation, PET-CT was the more sensitive test to find metastatic lesion than conventional assessment in 12 (50.0%). Baseline sSUV and mSUV was not significantly different between clinical responders and non-responders. After 2 cycles of chemotherapy, sSUV and mSUV was more decreased in clinical responder with significance (P=.023 and .020, respectively). In the 22 evaluable patients, PET responses were as followed: CMR in 1 (4.5%), PMR in 11 (50.0%), SMD in 7 (31.8%) and PMD in 3 (12.0%). Estimated median PFS was significantly prolonged in metabolic responders: PMR 8.3 months, SMD 4.7 months and PMD 2.3 months (P=.040). Patient with CMR had no evidence of progression for 14.7 month follow-up. Conclusions: In patients with mCRC, sequential FDG-PET predicted PFS and was more accurate than clinical response criteria. FDG- PET appears to be a promising tool for early prediction of response to chemotherapy.

No significant financial relationships to disclose.
Single nucleotide polymorphisms (SNPs) analysis of CYP2C8, GSTT1, GSTP1, MDR1(A), MDR1(B) and ERCC1 as predictor of survival after weekly paclitaxel for relapsed advanced head & neck cancer patients (AHNCP)
Authors: Grau J. J. , Monzo M. , Vargas M. , Jansa S. , Campayo m. , Alos L. , Domingo-Domenech J. , Verger E.
Published: March 2020

2540

Background: Gene SNPs correlate with survival in cancer patients (pts) treated with chemotherapy (CHM). CYP2C8 and GSTT1, GTSP1 genes are involved in phase 1 and 2 drug cellular metabolisms respectively; MDR1(A) and MDR1(B) are involved in drug membrane transport and ERCC1 in DNA repair Methods: We evaluated the presence of SNPs of these 6 genes and the survival of AHNCP treated with weekly paclitaxel, 80 mg/m2 iv for 6 weeks. Responding pts continue CHM till progression. All pts were cisplatin resistant and no other local therapies were available. We analysed paraffin-embedded biopsies from 47 consecutive AHNCP for SNPs of the mentioned genes. The status of the alleles wild type (wt) or at least 1 SNP was compared with response rate (RR), time to progression (TTP) and overall survival (OS) Results: Of 47 pts, 43 were male and 4 female. The median of age was 57 yr (46–80). RR was 45% (21/47) and the TTP in responders was 5 months of median. OS for all pts was 5.6 months. Wild type vs at least 1 SNPs frequencies according the genes were: CYP2C8 23/24; GSTT1 45/2; GSTP1 36/11; MDR1(A) 21/28; MDR1(B) 13/34; and ERCC1 27/20. OS was significantly better in pts with 2 or more SNPs accumulated (p=0.0455). No other significant differences were observed in RR, TTP or OS in SNPs vs wild type pts. Conclusions: SNPs of CYP2C8, MDR1(A) and MDR1(B) genes were more frequent than wt in our pts. OS was significantly better in pts with 2 or more SNPs accumulated. Paclitaxel provides high rate of responses of short duration in AHNC pts

No significant financial relationships to disclose.
Mechanism-based PKPD model for hepatoprotective effect of dexamethasone on transient transaminitis after trabectedin (ET- 743) treatment
Authors: Fetterly G. J. , Owen J. S. , Stuyckens K. , Passarell J. A. , Zannikos P. , Matos A. S. , Izquierdo M. A. , Perez-Ruixo J. J.
Published: March 2020

2545

Background: Reversible transient elevations in transaminases have been observed after trabectedin (T) administration, despite no alteration in plasma PK. A PKPD model was developed to evaluate the time course of ALT elevation, tolerance development, and covariate effects following different dosing schedules in cancer subjects. Methods: T was administered to 711 subjects as monotherapy (dose range: 0.024 - 1.8 mg/m2) as 1-, 3-, or 24-hr infusions every 21 days; 1- or 3-hr infusions on days 1, 8, and 15 every 28 days; or 1-hr infusions daily for 5 consecutive days every 21 days. Population PKPD modeling was performed with covariate evaluation [dexamethasone use (469/711 pt), ECOG PS scores (89.7% pts = 1), and BW (36–122 kg)] on PD parameters, followed by model validation. Simulations assessed the influence of dosing regimen and selected covariates on the time course of ALT and the effectiveness of the dose reduction strategy. Results: A precursor-dependent PKPD model described the temporal relationship between ALT elevation and T concentrations, where the transfer process of ALT from hepatocytes to plasma is stimulated by trabectedin plasma concentration. Overall, 66% of subjects had transaminitis. Mean predicted (%SEM) baseline ALT (ALTo) and T1/2 in plasma were 33 (5.5) U/L and 1.4 days, respectively. The magnitude of the T stimulation on the ALT transfer rate from hepatocytes to plasma was 11.2% per 100 pg/mL of trabectedin plasma concentration. Dexamethasone decreased the rate of T-induced ALT release from hepatocyte by 63% (p<0.001). Model validation results showed good concordance with the observed incidence of grade 3/4 toxicity. Simulations showed that severity of ALT elevation was dose- and schedule-dependent. The dose reduction strategy decreased the incidence of grade =3 toxicity by 13% and 39% following 2 and 4 cycles of therapy, respectively. Conclusions: A PKPD model quantifying the hepatoprotective effect of dexamethasone on transient and reversible transaminitis after T treatment has been developed. The model predicts that co-administration of dexamethasone and the suggested dose reduction strategy will enhance the safe use of T in the clinic.

No significant financial relationships to disclose.
Ratiometric dosing of irinotecan (IRI) and floxuridine (FLOX) in a phase I trial: A new approach for enhancing the activity of combination chemotherapy
Authors: Batist G. , Miller W. , Mayer L. , Janoff A. , Swenson C. , Louie A. , Chi K. , Chia S. , Gelmon K.
Published: March 2020

2549

Background: Like many pairs of chemotherapy agents, the combination of IRI and FLOX displays ratio-dependent activity in vitro. CPX-1, a liposome formulation of IRI:FLOX, was developed to maintain a synergistic 1:1 molar ratio in vivo, was highly active in preclinical models, and was evaluated in a phase 1 trial (CLTR0104–101). Methods: Doses were escalated from 30U/m2 (1U= 1 mg IRI + 0.36 mg FLOX) to 270 U/m2 given on day 1 and 15 of each 28 day cycle. Adult patients (pts) with advanced solid tumors, ECOG PS<2, adequate bone marrow, liver, and renal function were eligible; 4 pts per cohort. After defining the MTD, additional pts with CRC were enrolled (extension phase). IRI completed greater than 12 months prior to this trial was allowed in the absence of resistance to IRI. PK was done on day 1 and 15 of the 1st cycle. Results: Safety: The dose escalation phase enrolled 24 pts in 6 cohorts and added 2 pts in the 5th cohort (210U/m2; the MTD) after noting dose limiting diarrhea (3 pts) and neutropenia (1 pt) including one death from dehydration and renal failure due to prolonged diarrhea (gr3) & vomiting (gr2) at 270U/m2. An additional 7 pts with CRC received 210U/m2 in the extension phase. Grade 3/4 adverse events included diarrhea, nausea, vomiting, neutropenia and thrombocytopenia with most occurring at 270U/m2. No new toxicities were observed for this combination. Response: 30/33 pts were evaluable with 2 confirmed PRs (NSCLC and CRC), 21 SD and 7 PD. Median PFS was 5.4 mos. (0.3–11.8 mos.) in 15 pts w/CRC. PK: All pts maintained synergistic plasma IRI:FLOX ratios for 24h. IRI and FLOX AUCs (0-inf) were greater for CPX-1 than expected for conventional drugs. AUCs for SN-38 and 5FU at 210U/m2 were 0.8 ± 0.1 and 10 ± 8.7 μg-hr/mL, respectively, indicating bioavailability for both drugs. Conclusion: CPX-1 was well tolerated in the outpatient setting and evidence of anti-tumor activity was obtained. This is the first clinical evaluation of ratiometric dosing in which a synergistic drug ratio, pre-selected in vitro based on optimal anti-tumor activity, was maintained systemically to enhance therapeutic benefit.

[Table: see text]
Phase I study to determine the safety and pharmacokinetics of 4-hour intravenous infusion of TAS-106 on a once per week for 3 consecutive weeks every 28-day schedule in patients with solid tumors
Authors: Chadha R. , Mita A. , Iwasaki M. , Lassere Y. M. , Bogaard K. R. , Waldrum S. A. , Abbruzzese J. L. , Thomas M. B.
Published: March 2020

2556

Background: Most solid tumors are slow growing so the S-phase-specific anti-tumor drugs have limited efficacy. The antitumor nucleoside 3’-C-ethynylcytidine (ECyd, TAS-106) inhibits RNA synthesis by blocking RNA polymerases. In vitro, TAS-106 has demonstrated cytotoxicity 300 times greater than that of 5-FU against human lung, colorectal, gastric, pancreas and breast cancer cells. This trial was based on a previous clinical trial, in which study drug was administered as a bolus injection wkly for 3 consecutive weeks every 28- days and TAS-106 caused reversible dose-limiting peripheral neuropathy, and the safety dose was 1.32 mg/m2/dose. Methods: Objectives of this study were to determine the recommended phase II dose (RP2D) and the dose-limiting toxicity of TAS-106 administered by 4-hour IV infusion wkly for 3 consecutive weeks every 28-days; to investigate the clinical pharmacokinetics and pharmacodynamics of TAS-106, and document any antitumor activity observed. Results: A total of 18 patients (pts) were treated in the study; 16 pts were evaluable. The med age was 59; 11 female. A total of 44 courses of therapy were initiated by pts during the study; 39 courses (88.6%) were completed. Six pts had best tumor responses of stable disease (SD) and 9 pts had best tumor responses of progressive disease (PD); no pts had a complete or partial response. The mean duration of SD was 103.7 days. Median time to treatment failure was 57.0 days. At the RP2D (2.04 mg/m2/dose), 2 of 8 pts had best tumor response of SD with a mean duration of 132.0 days and three of the 8 pts had PD. For 12 pts (66.7%), adverse events (AEs) were considered to be related to TAS-106; the most commonly reported drug-related AEs were tremor (8 pts, 44.4%), neuropathy (4 pts, 22.2%), and peripheral neuropathy and fatigue (3 pts, 16.7% each) . No Grade 4 drug-related AEs were reported. Plasma concentrations increased with increasing dose, and at 2.04 mg/m2, the Cmax was 47.6±1.3 ng/mL. Conclusions: The safety profile of TAS-106 administered via wkly 4-hour IV infusion appears to be similar to the toxicity profile of TAS-106 when administered as a wkly bolus. In wkly 4-hour IV infusion, peripheral neuropathy was acceptable at the RP2D.

No significant financial relationships to disclose.
Effects of reduced glutathione (GSH) on oxaliplatin pharmacokinetics (OXA pk) and on Pt-DNA adducts formation in advanced colorectal cancer patients treated by FOLFOX4 regimen
Authors: Zanon C. , Airoldi M. , Passera R. , Cattel L. , Milla P. , Jaehde U. , Drescher A. , Branciforte L. , Gozzelino I. , Pedani F.
Published: March 2020

2559

Background: Neurotoxicity is a common OXA toxicity in FOLFOX4 regimen for patients with advanced colorectal cancer. Recently, Cascinu et al. (JCO 2002; 20: 3478–3483) provided evidence that GSH reduces the OXA-induced neurotoxicity, but GSH influence on the formation of Pt-DNA adducts still remains unknown. This study evaluated the effect of GSH addition on OXA pk and on Pt-DNA adducts formation Table of Contents Methods: 28 patients were given twelve FOLFOX4 courses and randomized to receive either GSH 1,500 mg/m2 or normal saline solution (placebo) before OXA iv infusion. OXA pk and Pt-DNA adducts formation were evaluated at courses 5, 9 and 12. Total and ultrafiltered platinum were analyzed by atomic adsorption, Pt-DNA adducts in leukocytes (as model for tumour tissue) by adsorptive stripping voltammetry. Pk analysis were done by non-compartmental analysis, statistical analysis by non-parametric Mann-Whitney test. Results: Median total and ultrafiltered platinum median Cmax and AUCtot values were comparable to previously reported ones, being higher in the placebo arm, due to a moderate reduction of platinum clearance. The formation of Pt-DNA adducts was more pronounced in GSH arm (median value 20.3 Pt atoms/106 nucleotides vs. 5.7 Pt atoms/106 nucleotides), even not statistically significant. Conclusions: The addition of GSH to FOLFOX4 regimen is able to reduce the OXA-induced neurotoxicity, without affecting either the OXA pk behaviour or the formation of Pt-DNA adducts, without modifying FOLFOX4 clinical efficacy.

[Table: see text]

No significant financial relationships to disclose.
The complete phase Ib clinical trial: A method to accelerate new agent development
Authors: Von Hoff D. D. , Nieves J. A. , Vocila L. K. , Weitman S. D. , Cvitkovic E.
Published: March 2020

2562

Background: The usual clinical development plan for a new agent (NA) includes a phase I monotherapy trial. However, because many new agents are eventually developed as part of a combination, additional phase I trials assessing the new agent in combination with a standard agent are usually performed (usually as individual phase Ib studies). Our hypothesis was that within a single protocol, several combination phase I trials could be conducted simultaneously. Methods: The design of the protocol is (assuming the new agent is synergistic with an anthracycline, a tubulin interactive agent, an antimetabolite, an angiogenesis inhibitor or an antibody to EGFR): patients with advanced cancer are treated with the combination deemed most likely to be of help-with a choice of a) anthracycline + NA; b) tubulin interactive + NA; c) antimetabolite + NA; d) angiogenesis inhibitor + NA; e) antibody to EGFR + NA. The standard agent is started at full dose with 3 patients placed at 1/3 full dose of NA, 3 patients at 2/3 dose of NA, and 3–6 patients at full dose of the NA in the combination. Results: Our experience with the complete phase Ib trial has found several advantages over conducting separate phase I trials. The advantages include: (a) a very rapid follow-up on preclinical data in one study; (b) a saving of time and expense in the start up; (c) accrual is rapid because many patients in a practice are likely to be eligible (e.g. the standard agent is the standard of care); (d) patients are often less pretreated; (e) the trial generates information for more informed selection of follow-up randomized phase II or III trials. Conclusions: Utilizing a Complete phase Ib trial design is feasible. Our initial experience has suggested that this approach is safe and highly efficient with several potential advantages over multiple sequential combination phase Ib studies.

No significant financial relationships to disclose.
Age-related effects on the pharmacodynamic (PD) relationship between STEALTH liposomal CKD-602 (S-CKD602) and monocytes in patients with refractory solid tumors
Authors: Maruca L. J. , Ramanathan R. K. , Strychor S. , Zamboni B. A. , Ramalingam S. , Edwards R. P. , Kim J. K. , Bang Y. J. , Lee H. P. , Zamboni W. C.
Published: March 2020

2576

Background: STEALTH liposomal CKD-602 (S-CKD602), a camptothecin analogue, is eliminated by the reticuloendothelial system (RES), which consists of cells including monocytes. CKD-602 released from S-CKD602 is eliminated by the kidney. Therefore, we evaluated the PD relationship between monocyte and absolute neutrophil counts (ANC; as a control) in blood and S-CKD602 and non-liposomal CKD-602 (NL-CKD602) in patients (pts) with refractory solid tumors. We also evaluated the effect of age on these relationships. Methods: In a phase I study, S-CKD602 was administered IV x 1 q 3 wk at 0.1 to 2.5 mg/m2. In phase I and II studies, NL-CKD602 was administered IV qdx5d q 3 wk at 0.5 to 0.9 mg/m2/d and 0.5 mg/m2/d, respectively. The % decreases in ANC and monocytes at nadir were calculated. For S-CKD602, pharmacokinetic studies of encapsulated (E), released (R), and sum total (ST=E+R) CKD-602 in plasma and ST in urine were performed and measured by LC-MS/MS. Area under the plasma concentration versus time curve (AUC) was calculated. Results: For S-CKD602 in all pts (n = 27), the % decrease in ANC and monocytes were 42 ± 30 % and 58 ± 34 %, respectively (P = 0.003). For S-CKD602 in pts < 60 years old (yo) (n = 12), the % decrease in ANC and monocytes were 43 ± 31% and 58 ± 26 %, respectively (P = 0.001). For S-CKD602 in pts = 60 yo (n = 15), the % decrease in ANC and monocytes were 41 ± 31% and 45 ± 36 %, respectively (P = 0.50). For NL-CKD602 (n = 42), % decrease in ANC and monocytes were similar (P > 0.05). For S-CKD602, the relationship between % decrease in monocytes and released CKD-602 AUC in plasma in pts < 60 yo (R2 = 0.54) and = 60 yo (R2 = 0.49) was similar. For S-CKD602, the relationship between the % decrease in monocytes and the amount of CKD-602 recovered in the urine was stronger in pts < 60 yo (R2 = 0.82) compared with = 60 yo (R2 = 0.30). Conclusions: Monocytes are more sensitive to S-CKD602 compared with neutrophils and the increased sensitivity is related to the liposomal formulation and not CKD-602. These results suggest that monocytes engulf S-CKD602 which causes the release of CKD-602 from the liposome and toxicity to the monocytes, and that the effects are more prominent in pts < 60 yo.

[Table: see text]
A randomized, controlled, double-blind phase III study (AVOREN) of bevacizumab/interferon-α2a vs placebo/interferon- α2a as first-line therapy in metastatic renal cell carcinoma
Authors: Escudier B. , Koralewski P. , Pluzanska A. , Ravaud A. , Bracarda S. , Szczylik C. , Chevreau C. , Filipek M. , Melichar B. , Moore N.
Published: March 2020

3

Background: Bevacizumab (BEV) is a monoclonal antibody that inhibits tumor angiogenesis by targeting VEGF. In relapsed RCC, BEV improved time to progression compared with placebo (2.5 vs. 4.8 months). A phase III trial was conducted to evaluate the efficacy and safety of BEV in combination with interferon (IFN)-a2a as first-line treatment in metastatic (m) RCC. The final analysis of progression-free survival (PFS) and interim analysis of overall survival (OS) are presented. Methods: Nephrectomized patients with clear cell mRCC, KPS of =70%, no CNS metastases and adequate organ function received IFN- a2a (x3/week at a recommended dose of 9 MIU for up to 1 year) plus BEV (10mg/kg q2w) or placebo until disease progression. Tumor assessments were performed every 8 weeks until week 32 and 12 weekly thereafter. Patients were stratified according to country and Motzer score. Results: Between June 2004 and October 2006, 649 patients were randomized (641 treated) at 101 centers in 18 countries. The treatment arms were well balanced for prognostic factors. At the data cutoff, 505 progression events had occurred, 111 patients remained on treatment, 287 had discontinued (discontinuations due to AEs were 12% with IFN vs. 28% with IFN-a2a/BEV), and 251 died. BEV-related side effects were generally mild and consistent with previous observations. The addition of BEV to IFN-a2a significantly increased PFS (10.2 vs. 5.4 mo) (HR=0.63; p<0.0001) and objective tumor response rate (30.6% vs. 12.4%; p<0.0001). A trend toward improved OS was observed with the addition of BEV to IFN-a2a (p=0.0670). Conclusions: BEV improves PFS when combined with IFN-a2a in mRCC. No unexpected safety events were observed.

[Table: see text]

[Table: see text]
Combination immunotherapy with GM-CSF and CTLA-4 blockade for hormone refractory prostate cancer: Balancing the expansion of activated effector and regulatory T cells
Authors: Fong L. , Kavanagh B. , Hou Y. , O’Brien S. , Valiente J. , Weinberg V. , Rini B. I. , Small E. J.
Published: March 2020

3001

Background: CTLA-4 is a costimulatory molecule expressed on activated T cells that delivers an inhibitory signal to these T cells. CTLA4 blockade with antibody treatment has been shown to augment T cell responses and anti-tumor immunity in animal models. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a bone marrow growth factor for antigen presenting cells, which has also been shown to enhance anti-tumor immune responses. Methods: A phase I trial in patients with metastatic, hormone refractory prostate cancer (HRPC) was undertaken to combine these immunotherapies. Sequential cohorts of 3–6 patients were treated with escalating doses (0.5, 1.5 or 3 mg/kg) of ipilimumab, a fully human anti-CTLA-4 antibody, given IV on day 1 of each 28-day cycle × 4 cycles. Patients also received GM-CSF 250 mg/m2/d SC on days 1–14 of the 28-day cycles. Patients were monitored for toxicity as well as for T cell activation. PSA and radiographic tests were performed at baseline and through therapy to evaluate for clinical response. Results: 24 patients have been treated. Of 6 patients treated on the highest dose level (3 mg/kg ×4), 3 (50%) had confirmed PSA declines of >50%, and one of these patients had a partial response in hepatic metastases. Immune-related adverse events associated with ipilimumab treatment consisted of a grade 3 rash in 1 patient at 1.5 mg/kg, a grade 3 rash and panhypopituitarism in 1 patient at 3.0 mg/kg, and a grade 3 colitis in one patient at 3.0 mg/kg. All events were successfully managed. A dose-response relationship was seen between ipilimumab dose and effector T cell activation. Expansion of circulating CD4+ FoxP3+ regulatory T cells was also seen with treatment. Conclusions: CTLA-4 blockade combined with GM-CSF treatment induces clinical responses in HRPC. Treatment induces both the expansion of activated effector and regulatory T cells in vivo in cancer patients. Finally, CD4 and CD8 T cell activation, adverse events, and clinical responses appear to be dose-dependant. Supported by NIH SPORE P50 CA89520.

No significant financial relationships to disclose.
Phase II trial of vaccination with WT1 peptide, GM-CSF, and KLH in patients with acute myeloid leukemia and myelodysplasia: Final immunological, molecular, and clinical results
Authors: Letsch A. , Scheibenbogen C. , Busse A. , Asemissen A. M. , Schmittel A. , Hofmann W. K. , Uharek L. , Blau I. W. , Thiel E. , Keilholz U.
Published: March 2020

3008

Purpose: A phase II trial of vaccination with the HLA-A2-restricted WT1.126–134 peptide was performed in patients (pts) with AML and MDS and overexpression of WT1 to determine toxicity, immunogenicity, and molecular and clinical activity. Methods: Patients received intra/subcut. vaccinations of 0.2 mg WT1.126–134 peptide (day 3), 62.5 mcg GM-CSF (days 1–4) as DC-stimulant and 1 mg keyhole limpet hemocyanin (day 3) as T helper protein. Vaccination was biweekly x 4 followed by 4-weekly in the first 13 patients and continuously biweekly in the subsequent 13. Early disease progression until vaccine # 6 was allowed, if not requiring chemotherapy. WT1-specific T cell responses were measured by tetramer and cytokine flow cytometry. WT1 levels were assessed by qRT-PCR. Clinical response assessment followed IWG-MDS criteria, capturing stable disease and hematologic improvement. Statistical analysis was performed by frequency tables and exploratory comparisons using Fishers test. Results: Of 29 pts enrolled 25 were evaluable, 23 with AML and 2 with RAEB. 15 AML pts had >5% marrow blasts and 8 had high-risk CR with detectable WT1 mRNA. A median of 11 (range 3 - 25) vaccinations was administered, 3 pts are ongoing. No relevant toxicity occurred. There were no obvious differences in outcome parameters between the 2 vaccination schedules. The percentage of patients with WT1 tetramer response increased from 28% prior to vaccination to 80% at week 10 (p=0.003), while the WT1 peptide specific cytokine response increased from 20% to 57% (p=0.012) of patients. WT1 mRNA-levels increased in 22% of patients, were stable in 26%, and decreased in 52% (2 to>50-fold). One CR (514 days) and 13 SD (99 to 339 days) were observed, 5 SD with >50% blast reduction and 3 with hematologic improvement. The CR and 3 SD occurred after initial PD. The median time to treatment failure (TTF) was 143 days. There was a significant association between decrease in WT1 mRNA levels and TTF (p=0.026). Conclusions: This study proves immunological, molecular and clinical efficacy of WT1 peptide vaccination in AML. Further investigations are indicated in WT1 expressing carcinomas and in combination with agents targeting CTLA4 or PD1.

No significant financial relationships to disclose.
Booster vaccination of non-small cell lung cancer (NSCLC) patients with MAGEA3 protein and AS02B adjuvant
Authors: Atanackovic D. , Altorki N. K. , Cao Y. , Ritter E. , Ferrara C. , Ritter G. , Hoffman E. W. , Bokemeyer C. , Old L. J. , Gnjatic S.
Published: March 2020

3015

Background: We have previously reported results of a phase II trial of recombinant ProtD/MAGE-3/His (MAGEA3) protein 300μg administered IM every three weeks for 4 doses with or without adjuvant AS02B to NSCLC patients following resection of MAGEA3 positive disease (JI, 172:3289, 2004). We found that the presence of adjuvant was essential for the development of strong humoral and cellular responses against selected MAGEA3 epitopes. Methods: 14 of the original 18 patients received booster vaccinations. Patients who still had no evidence of disease for up to two years after receiving their original MAGEA3 protein regimen (7 in cohort 1 without adjuvant, 7 in cohort 2 with adjuvant), received 4 additional doses of MAGEA3 protein with adjuvant. T cell immunomonitoring was extended to encompass any MAGEA3 epitope using full length antigen, and the scope of analysis of humoral responses was widened. Results: After just one boost injection, 6 of the 7 patients originally vaccinated with MAGEA3 protein plus adjuvant reached the peak of antibody titers to MAGEA3 attained during the first vaccination and went on to develop a stronger response than during the first cycle. In addition, the spectrum of CD4+ and CD8+ T cells against various new and known epitopes widened with booster vaccination. In contrast, only 3/7 patients originally vaccinated with MAGEA3 protein alone seroconverted to low-titered MAGEA3 responses and showed very limited CD4+ and no CD8+ T cell reactivity, despite now receiving antigen in the presence of adjuvant. Conclusions: These results underscore the importance of proper antigen priming using an adjuvant for generating persistent B and T cell memory, allowing for typical booster responses with re-immunization. In contrast, absence of adjuvant at priming may compromise further immunization attempts. These data provide immunological rationale for vaccine design in light of recently reported favorable clinical findings in NSCLC patients following vaccination with MAGEA3 protein plus adjuvant AS02B (GSK, ASCO 2005).

No significant financial relationships to disclose.
Correlation of T-cell response, clinical activity and regulatory T-cell levels in renal cell carcinoma patients treated with IMA901, a novel multi-peptide vaccine
Authors: Singh-Jasuja H. , Walter S. , Weinschenk T. , Mayer A. , Dietrich P. Y. , Staehler M. , Stenzl A. , Stevanovic S. , Rammensee H. , Frisch J.
Published: March 2020

3017

Background: Cancer vaccines have been able to induce T-cell responses in cancer patients but rarely demonstrated a correlation of immune responses with clinical benefit. Here, we present immunological results of a phase 1 study with IMA901, a therapeutic cancer vaccine based on multiple novel synthetic tumor-associated peptides (TUMAP) identified as being naturally presented in primary renal cell carcinoma (RCC) tissues. Methods: The HLA peptidome of 32 primary RCC samples was systematically investigated using a combination of mass spectrometry, gene expression profiling and in vitro human T-cell assays. 9 HLA-A*02- and 1 HLA-DR- restricted TUMAPs derived from 9 different tumor antigens were selected and designated IMA901. 28 HLA-A*02-positive stage III/IV RCC patients were enrolled in a single arm, multicenter study and received 8 vaccinations on days 1, 2, 3, 8, 15, 22, 36, and 64 each consisting of 4.5 mg IMA901 (including a HBV-derived viral marker peptide) and 75 μg GM-CSF as immune adjuvant. T-cell responses using IFN-γ ELISPOT and HLA multimer analysis and CD4+ Foxp3+ regulatory T cell (Treg) levels were measured in peripheral blood. Results: In vivo IMA901- induced specific T-cell responses were detected to the HBV marker peptide (52% of 27 evaluable patients), at least one TUMAP (74%) or multiple TUMAPs (30%). T-cell responses were detectable already at day 15, peaked subsequently and were sustainable until follow-up in the majority of patients. Most importantly, patients eliciting multiple responses to TUMAPs significantly showed a higher clinical benefit rate (SD+PR; p=0.018) and lower Treg levels at study onset (p=0.016). No correlation of HBV marker peptide responses with either clinical benefit or Treg levels was observed. Conclusions: IMA901 rapidly induced T-cell responses in a majority of advanced RCC patients. A clinical mode of action is strongly supported by the significant correlation of multiple T-cell responses with clinical benefit. CD4+ Foxp3+ Tregs seem to play an active role in limiting the broadness of T-cell responses. Furthermore, our data suggest that we can predict in vivo immunogenicity of cancer vaccine antigens by our in vitro drug discovery approach.

No significant financial relationships to disclose.
Covalent coupling of a novel TLR7 agonist to antigen elicits an effective immune response in a murine melanoma tumor model
Authors: Daniels G. A. , Chan M. , Wu C. C. , Tawatao R. , Messmer D. , Eftimie B. , Cottam H. , Carson D.
Published: March 2020

3019

Background: Toll-like receptor (TLR) signaling triggers innate immune stimulation capable of generating an adaptive immune response under appropriate conditions. TLR agonists have shown efficacy in preclinical and clinical cancer therapies. However, one limitation to this approach has been the use of TLR agonists delivered at distances away from the target (ie-subcutaneous injections for general immune stimulation) or the inability to effectively couple antigen with adjuvant. Methods: We have synthesized a novel TLR7 agonist capable of covalent coupling to primary amines under physiologic conditions. In vitro activity of adjuvant alone or antigen-adjuvant complexes were tested for innate immune activation by utilizing bone marrow-derived murine or peripheral blood mononuclear cell-derived dendritic cells (DC) with respect to DC maturation and cytokine secretion (IL12, IL6, TGFbeta and IFNgamma). Immunocompetent syngeneic C57/b6 mice were prophylactically vaccinated with intradermal with either antigen, antigen mixed with adjuvant or antigen- adjuvant coupled complexes and challenged with B16 melanoma tumor cells expressing the cOVA transgene. Results: The effective concentration (EC50) for each compound generally followed a bell shaped distribution with higher doses being inhibitory. Maximal stimulation occurred between 10 and 1000nM. Coupled adjuvant molecules retained activity with generally lower EC50 values. Coupling 1V199 to chicken ovalbumin nearly doubled median survival from 22 to 35 days following subcutaneous tumor challenge compared with chicken ovalbumin alone. Conclusions: Covalent linkage of a TLR7 agonist to antigen stimulates DC cytokine production and protects mice from tumor challenge. Use of a soluble TLR7 agonist which retains its immune stimulating properties following coupling to antigen under physiologic conditions may be useful in the development of an in situ vaccine in solid tumor therapy.

No significant financial relationships to disclose.
A pilot study of bevacizumab (Bev) and continous low-dose granulocyte-macrophage colony-stimulating factor (GM-CSF) in heavily pretreated patients with refractory solid tumors: Preliminary results
Authors: Schmidt M. , Reinhold U. , Kurbacher J. A. , Rieckmann O. , Huncke H. , Radmacher A. , Cree I. A. , Kurbacher C. M.
Published: March 2020

3031

Bev is an important inhibitor of VEGF, a mediator of tumor-induced angiogenesis. Inhibiting generation of dendritic cells (DC) from blood and tissue precursors, VEGF is also a crucial immunosuppressive agent in anti-tumoral immunotolerance. Beyond anti-angiogenesis, inhibition of VEGF may results in an improved antineoplastic immune response, which may be further improved by GM-CSF known to effectively stimulate DCs. GM-CSF has formerly be shown to induce objective responses in refractory gynecologic and breast carcinomas [Kurbacher et al. Oncology 2005]. This ongoing prospective clinical trial was initiated to investigate the combination of Bev and GM-CSF in patients (pts) with heavily pretreated solid tumors. Toxicity was documented according to the NCI-CTC scale, responses were recorded according to the RECIST or the Rustin criteria. Statistical pre-study considerations forced termination of the trial if no responses were observed among the first 12 pts recruited. Until now, 10 pts are included: epithelial ovarian carcinoma, n=4; metastatic breast cancer, n=3; peritoneal papillary-serous carcinoma, n=2; salivary gland adenocarcinoma, n=1. Regarding their history, all pts have been considered chemo-resistant or non-treatable due to their underlying bone marrow and/organ functions. Bev was applied at a fixed dose of 6 mg/kg q2w. GM-CSF was administered sc at 125 μg/d. GM-CSF was increased every 4 weeks at 25 μg/d increments until a maximum dose of 250 μg/d until occurence of objective tumor response or leukocytosis <20,000 cells/μL. Among the 10 pts treated so far, 2 partial responses (PR), 5 stable diseases (SD), and 3 progressive diseases (PD) have been recorded accounting for an objective response rate of 20%. Median time to progression is 16 weeks, with 7 pts still alive. Toxicity was generally mild and never therapy-limiting: NCI-CTC grade (G) 2 fatigue in 3 pts, G2 flu-like symptoms and G2 in either 1 pt, G1 injection site reactions in 3 pts. Preliminary results of this trial have shown Bev plus GM-CSF to produce a promising clinical activity in heavily pretreated pts with solid tumors. Thus, pts accrual is still continuing.

No significant financial relationships to disclose.
Generation of antibodies that target and kill MUC1 expressing cancer cells via a novel cell-tethered MUC1 α/β junction epitope
Authors: Karmely M. , Rubinstein D. B. , Wreschner D. H.
Published: March 2020

3034

Background: MUC1 protein has generated considerable interest as a target for tumor killing. However, a serious shortcoming of anti-MUC1 antibodies generated to date is that they recognize epitopes within the strongly immunogenic tandem-repeat-array of the MUC1 a- chain which is released from the cell into the circulation. Soluble shed MUC1 a-chain sequesters anti-tandem-repeat-array antibodies, severely limiting their ability to reach MUC1-expressing malignant cells. Rather than target freely circulating MUC1 a-chain, we identified the junction of the MUC1 a-subunit to cell-membrane-bound MUC1 β-subunit as a preferable cell-tethered MUC1 epitope; since the site is not shed, antibodies recognizing it are more effective in targeting MUC1 expressing cells. Methods: To circumvent the immunogenicity of the a-chain tandem repeat array we formulated a novel antibody generating protocol utilizing immunization with both MUC1 cDNA and with the alternatively-spliced MUC1/X protein isoform from which the tandem repeat array is deleted. After immunization and hybridoma formation, anti- MUC1 a/β junction antibodies were selected. Results: DMC209 monoclonal antibodies uniquely specific for the MUC1 a/β junction were generated. The antibodies specifically bind the MUC1 a/β junction on full-length MUC1 expressed by breast and ovarian cancer cells, and on MUC1-positive malignant plasma cells of multiple myeloma. To demonstrate that anti-MUC1 a/β junction antibodies kill malignant cells, immunotoxin conjugates were formed with anti-MUC1 a/β junction polyclonal antibodies generated in our cDNA/protein immunization protocol and PE38, a powerful pseudomonas exotoxin. The antibody-exotoxin conjugates were potently cytocidal to MUC1-expressing malignant cells. Significantly, cell killing was abrogated by addition of soluble MUC1/X protein, highlighting that the cell-killing immunotoxin gains cell entry via the MUC1 a/β junction. Conclusions: The MUC1 a/β junction has been identified as an important cell-tethered MUC1 epitope against which highly specific antibodies can be generated capable of killing MUC1-expressing cells. These studies point to effective anti-MUC1-based immuno-therapeutic strategies.

No significant financial relationships to disclose.
Natural history of diarrhea associated with the anti-CTLA4 monoclonal antibody CP-675,206
Authors: Antonia S. , Sosman J. , Kirkwood J. M. , Redman B. , Gajewski T. F. , Pavlov D. , Bulanhagui C. , Camacho L. H. , Ribas A.
Published: March 2020

3038

Background: Diarrhea resulting from immune activation has been associated with CTLA4 blockade. For example, in patients (pts) with stage IV melanoma receiving ipilimumab (MDX-010), a number of pts developed grade 3/4 autoimmune enterocolitis and severe diarrhea (Attia et al, 2005). In a single-dose phase I trial of CP-675,206 at doses up to 15 mg/kg in pts with solid tumors (n = 39), 9 instances of diarrhea were reported including 3 grade 3 events (Ribas et al, 2005). The incidence and severity of diarrhea was assessed in pts receiving CP- 675,206 in a large phase I/II study. Methods: An open-label phase I/II trial of CP-675,206 was conducted in pts with stage III (unresectable) or stage IV melanoma and an ECOG PS = 1. Diarrhea was assessed in pts treated at the phase II doses: 10 mg/kg monthly (Q1M) in phase I (n = 22), or 10 mg/kg Q1M (n = 44) or 15 mg/kg every 3 months (Q3M, n = 45) in phase II. Results: Medians of 3.5 doses (range, 1 to 18) at 10 mg/kg Q1M in phase I, 3 doses (range, 1 to 26) at 10 mg/kg Q1M in phase II, and 1 dose (range, 1 to 9) at 15 mg/kg Q3M were administered with 100% dose compliance. Treatment-related diarrhea was reported by 43 (39%) of 111 pts, and grade 3 diarrhea occurred in 14 (13%) pts. One patient had grade 4 colitis resulting in a colectomy. Diarrhea (all grades) occurred with similar frequency in each dose group; however, grade 3 treatment-related diarrhea occurred in 8% of pts treated with 15 mg/kg Q3M compared with 18% of pts treated with 10 mg/kg Q1M in phase I and 14% of pts treated with 10 mg/kg Q1M in phase II. Among 9 pts with an objective response, 8 experienced diarrhea (3 of which were grade 3). The majority of cases (65%) were mild to moderate in severity with a median time to onset of 51 days (range, 1 to 583 days) and resolution of 8 days (range, 1 to 182 days). More than half of pts who reported serious events of diarrhea were treated with steroids. Conclusions: Diarrhea associated with CP-675,206 was primarily mild to moderate in severity, transient, and manageable. In addition, 15 mg/kg Q3M may be better tolerated than 10 mg/kg Q1M. Ongoing clinical trials in pts with advanced melanoma will provide further information about the incidence, severity, and optimal management of diarrhea associated with CP-675,206.

No significant financial relationships to disclose.
Combining galiximab with the chemotherapeutic agents fludarabine or doxorubicin improves efficacy in animal models of lymphoma
Authors: Hariharan H. K. , Murphy T. , Clanton D. , Berquist L. , Chu P. , Yun T. , Molina A. , Ho S.
Published: March 2020

3040

Background: Galiximab, a primatized monoclonal antibody that binds with high affinity to CD80 and mediates antibody- dependent, cell-mediated cytotoxicity in vitro, is currently under investigation for the treatment of follicular non-Hodgkin’s lymphoma (NHL). In a phase I/II monotherapy study, galiximab produced an overall response rate of 11%, and tumor reductions were observed in 46% of patients. Initial clinical trials also demonstrate that galiximab is well tolerated and suggest that combining galiximab with rituximab (anti-CD20) provides clinical benefit. These results are consistent with preclinical studies in murine lymphoma xenograft model systems, which demonstrate the superiority of combination therapy. Methods: To further define the therapeutic potential of galiximab, the Raji subcutaneous and the SKW disseminated lymphoma murine xenograft models were used to define the in vivo efficacy of galiximab alone or in combination with fludarabine or doxorubicin. Similar studies were performed with rituximab. Results: In the Raji model, both galiximab and rituximab exhibited maximal inhibition of the growth of preestablished (150-mg) tumors at a dose of 3 mg/kg/wk. Interestingly, higher doses of galiximab (but not rituximab) showed reduced inhibition. Galiximab (3 mg/kg/wk) inhibited tumor growth alone (P<0.0001 vs. control) and showed significantly enhanced activity when combined with fludarabine (50 or 100 mg/kg daily for 5 days; P<0.0002 vs. galiximab alone and P<0.003 vs. fludarabine alone). Similar results were observed with rituximab. In the SKW model, treatment with galiximab (5 mg/kg/wk for 6 doses) significantly enhanced survival compared with a control (P<0.0001) or doxorubicin (2.5 mg/kg/day for 3 doses; P<0.0001). Studies combining fludarabine or doxorubicin with both galiximab and rituximab are ongoing. Conclusions: Studies in animal models of lymphoma indicate that galiximab may provide clinical benefit when used in combination with chemotherapeutic agents such as fludarabine and doxorubicin, and provide a rationale for the investigation of these novel chemoimmunotherapy combinations in clinical trials.

No significant financial relationships to disclose.