bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacodynamic assessment of INCB024360, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), in advanced cancer patients.
Authors: Newton Robert Charles , Scherle Peggy A , Bowman Kevin , Liu Xiangdong , Beatty Gregory Lawrence , O'Dwyer Peter J , Gajewski Thomas , Bowman Jill , Schaub Richard , Leopold Lance
Published: March 2020

2500^

Background: The ineffectiveness of the immune system to control tumor growth is, in part, a result of immunosuppression imposed by negative regulatory mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme that catabolizes the first and rate-limiting step in the degradation of the essential amino acid tryptophan (Trp) to kynurenine (Kyn), has been shown preclinically to play an important role in tumor-mediated immunosuppression. In cancer patients (pts), elevated IDO1 levels are associated with poor prognosis and shortened survival in a number of tumor types. Here we describe the pharmacodynamic (PD) assessment of INCB024360, a novel inhibitor of IDO1. Methods: Plasma samples were obtained from consented pts in study INCB 24360-101, a phase I dose-escalation study in patients with advanced malignancies. Trp and Kyn levels in plasma were determined by LC/MS/MS. IDO1 activity in activated peripheral blood cells was also monitored. Results: Using anti-IDO1 specific antisera and archived tumor samples, we found IDO1 expression in various human tumors, including ovarian, colorectal, breast and prostate. Consistent with this result, higher Kyn/Trp ratios (1.5-3.4 fold above healthy volunteers) were detected in archived plasma samples from pts, indicative of higher IDO1 activity in cancer pts. To date, 23 pts have been treated with the selective IDO1 inhibitor INCB024360. When plasma samples from patients were collected pre- and post-INCB024360 treatment, significant dose-dependent reductions in plasma Kyn/Trp ratios and Kyn levels were detected. As an additional biomarker measurement, whole blood samples collected from pts at various times after dosing were stimulated ex vivo with interferon-γ and lipopolysaccharide to increase IDO1 activity and also showed dose-dependent decreases in IDO activity. With the current dose regimens and assays we have successfully achieved sustained inhibition of >90% at a well tolerated dose of INCB024360. Conclusions: This is the first demonstration of PD activity of an IDO1-specific inhibitor in cancer pts. Our study also confirms that IDO1 is frequently activated in cancer pts. The methods described will be used to establish a phase II dose.
From bench to bedside: The use of the li-Key technology to improve helper peptides for clinical use in cancer vaccines.
Authors: Vreeland Timothy J , Hale Diane F , Sears Alan K. , Clifton Guy T. , Pappou Efi , Dabney Raetasha Sheavette , Ardavanis Alexandros , Patil Ritesh , Ponniah Sathibalan , Anastasopoulou Eleftheria , Perez Sonia A. , Shumway Nathan M. , Peoples George Earl , Mittendorf Elizabeth Ann
Published: March 2020

2508

Background: Work involving peptide vaccines has shown that peptides containing MHC Class II epitopes, which elicit CD4+ T cell responses, may play a role in potentiating an immune response. The Ii-Key peptide (amino acids 77-80 of the immune-regulatory Ii protein), when covalently linked to an MHC Class II epitope, can induce conformational change in the epitope binding groove, increasing CD4+ T cell stimulation up to 250 fold. Here we present an update of results from clinical trials evaluating this novel technology in an adjuvant breast cancer vaccine targeting HER2/neu. Methods: We reviewed our trials investigating AE37, a hybrid peptide created by the addition of the Ii-Key peptide (LRMK) to AE36 (GVGSPYVSRLLGICL), an MHC Class II-binding peptide from the intracellular domain of the HER2 protein. We have completed a phase I study and are currently conducting a randomized phase II trial of the AE37 peptide + GM-CSF in the adjuvant treatment of disease-free breast cancer patients with any level of HER2 expression (IHC 1-3+ or FISH>1.2). Results: Phase I data showed the vaccine to be safe and effective in raising anti-HER2 immunity. Importantly, even the cohort of patients given AE37 without GM-CSF showed significant increases in both in vivo and in vitro immune responses. To date, we have enrolled 201 patients to our phase II trial (Vaccine (VG)=103, Control (CG)=98). Toxicity has been minimal (99% of local and systemic toxicities grade ≤2). VG patients have shown significant increases in both in vivo and in vitro responses to both AE36 and AE37, with consistently stronger responses to the AE37 hybrid peptide than the native AE36. With a median f/u of 22 months, Kaplan Meier projections estimate recurrence rates of 10.3% in the VG compared to 18% in the CG; a 43% risk reduction. Conclusions: The AE37 peptide vaccine appears to be effective in eliciting a strong immune response and possibly preventing breast cancer recurrence. These results provide an important proof of concept and suggest that additional studies evaluating Ii-Key hybrid peptide vaccines are warranted, whether in the field of immunotherapy or more traditional vaccines.
PD-1/PD-L1 pathway as a target for cancer immunotherapy: Safety and clinical activity of BMS-936559, an anti-PD-L1 antibody, in patients with solid tumors.
Authors: Tykodi Scott S. , Brahmer Julie R. , Hwu Wen-Jen , Chow Laura Q. , Topalian Suzanne Louise , Hwu Patrick , Odunsi Kunle , Camacho Luis H. , Kauh John S , Pitot Henry Clement , Hamid Omid , Pardoll Drew M. , Agrawal Shruti , Parker Susan , Goldberg Stacie , Gupta Ashok Kumar , Wigginton Jon
Published: March 2020

2510

Background: Blocking the interaction between programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells, and its ligand PD-L1 may enhance T-cell function. Here we describe the safety and activity from the first clinical study of BMS-936559 in patients (pts) with advanced solid tumors, further validating the importance of the PD-1/PD-L1 pathway as a target for cancer therapy. Methods: BMS-936559 was given Q2 wk IV in a 6-wk cycle at doses of 0.3−10.0 mg/kg during dose escalation and/or cohort expansion; pts could receive up to 16 cycles (48 doses). Results: As of August 1, 2011, 162 pts with melanoma (MEL, n=53), non-small-cell lung (NSCLC, n=50), colorectal (n=18), renal cell (RCC, n=17), ovarian (n=17), and pancreatic (n=7) cancer were treated. Median therapy duration was 11 wks (max 99 wks). Common related adverse events (rAEs; ≥5% pts) included fatigue, diarrhea, infusion reaction, arthralgia, rash, and pruritus. The incidence of grade 3-4 rAEs was 8.6%. AEs of special interest included hypothyroidism, hepatitis, sarcoidosis, endophthalmitis, and myasthenia gravis; there were no drug-related deaths. Clinical activity was observed in MEL, RCC, and NSCLC. Objective responses (ORs; RECIST 1.0) were observed in heavily pretreated pts. ORs were durable; among 16 pts with ORs, 7 had responses lasting ≥1 yr. Two other pts had ongoing ORs with durations of 2.3 and 8.5 mo at data lock. Several pts had prolonged stable disease. Some pts had a persistent reduction in overall tumor burden in the presence of new lesions but were not categorized as responders. In NSCLC, ORs were observed irrespective of histology. Conclusions: BMS-936559 was active and generally well tolerated in pts with NSCLC, RCC, and MEL. In conjunction with data from anti-PD-1/BMS-936558 trials, this study concurrently validates the importance of the PD-1/PD-L1 pathway for cancer immunotherapy and supports further clinical development of anti-PD-1/PD-L1 directed therapy. [Table: see text]
Safety of the antimyostatin monoclonal antibody LY2495655 in healthy subjects and patients with advanced cancer.
Authors: Jameson Gayle S. , Von Hoff Daniel D. , Weiss Glen J. , Richards Donald A. , Smith David A. , Becerra Carlos , Benson Mitchell C. , Yuan Zheng , Robins Deborah A , Turik Michael , Wagner Margaret , Hu Leijun , Lin Boris K.
Published: March 2020

2516

Background: Skeletal muscle wasting (cachexia) is a prevalent and not readily managed condition in advanced cancer patients. LY2495655 is a humanized monoclonal antibody to myostatin, which has demonstrated positive effects on cachexia measures in animal models. We present phase I trial data on use of LY2495655 in healthy volunteers (Study 1) and interim data from an ongoing phase I study in patients with advanced cancer (Study 2). Methods: Study 1 was a randomized, placebo-controlled, blinded, single-dose, parallel, dose-escalation study evaluating the safety and tolerability of IV or SC LY2495655 (0.7 mg-700 mg). Study 2 is an ongoing nonrandomized, open-label study evaluating the safety and pharmacokinetics (PKs) of LY2495655 in patients with advanced cancer not receiving chemotherapy. Dose cohorts (2 mg-700 mg, ≥3 patients per cohort) were to be treated until the maximum tolerated dose (MTD) was met, or the highest dose (700 mg) cohort was completed. Final locked data from Study 1 and interim data from the dose escalation phase of Study 2 were used in the analyses. Results: In Study 1, 64 healthy volunteers were enrolled (48 LY2495655, 16 placebo). In Study 2, 22 patients had received treatment with LY2495655 at the time of the analysis. In both studies, all doses of LY2495655 were well tolerated (no DLTs were observed and MTD was not reached), and nonlinear PKs were observed (most evident in lower dose levels). In Study 1, thigh muscle volume generally increased with LY2495655. In Study 2, increased muscle volume was observed only at 21-mg and 70-mg doses. Consistent increases in hand grip strength and improvements in functional tests were observed at doses ≥21 mg. Conclusions: There were no unusual safety concerns in healthy subjects or cancer patients. PK results were consistent between the 2 studies. Increases in muscle volume were observed in both studies, with concomitant improvement in functional measures. However, there is no clear trend in dose-dependent efficacy, possibly due to extremely small sample sizes and patient heterogeneity. Enrollment in Study 2 continues with dose expansion cohorts. A Phase 2 study is ongoing in pancreatic cancer patients.
A phase I safety study of NPC-1C: A novel, therapeutic antibody to treat pancreas and colorectal cancers.
Authors: Arlen Philip M. , Diaz Luis A. , Azad Nilofer Saba , Sleer Leanne Sophia , Haley Sherri , Morse Michael
Published: March 2020

2517

Background: NPC-1C (NEO-101; Ensituximab) is a chimeric monoclonal antibody being developed as a novel biological treatment for pancreatic and colorectal cancers. This antibody was selected from a panel of hybridomas generated from mice immunized with semi-purified membrane-associated proteins derived from biologically screened, pooled human allogeneic colon cancer tissues. The NPC-1C target appears to be a variant of MUC5AC that is expressed specifically by human colon and pancreatic tumors with minimal cross-reactivity to normal GI tract tissues. Methods: A phase I open label, multi-center dose escalation clinical trial with NPC-1C has completed accrual of subjects with advanced pancreatic and colorectal cancer refractory to standard therapy. The primary objectives are to determine safety and tolerability of escalating doses of NPC-1C and to assess pharmacokinetics (PK) and select immune responses to the antibody at each dose level. Secondary objectives are to evaluate evidence of clinical benefit and to explore immunologic correlates Results: Three cohorts of subjects have been treated with NPC-1C at escalating dose levels of 1, 1.5, and 2 mg/kg IV every two weeks. All 15 subjects (10 colorectal, 5 pancreatic) have enrolled on study (5/15 non-evaluable). No DLT was noted at the 1mg/kg dose level with 2 of 3 patients showing stable disease at completion of Course 1. At the 2 mg/kg dose level, one patient demonstrated stable disease after course 1. At escalating rates of infusion, 3 subjects experienced mild to moderate hemolysis that resolved without intervention. All 6 patients who have received 1.5 mg/kg at a constant rate of infusion have been evaluated, with no dose limiting toxicity. One of 5 patients re-staged thus far in the 1.5 mg/kg cohort showed stable disease on scans after completing the first course of treatment (4 doses), and continued to receive additional doses. Preliminary data show no drug induced antibody responses in treated subjects. PK, HAMA and cytokine evaluation is ongoing. Conclusions: NPC-1C is tolerated well at the current dose level of 1.5 mg/kg every 2 weeks without producing any DLT We plan to continue accrual in the Phase 2A to evaluate clinical responses and additional safety data.
The immunological impact of the RAF inhibitor BMS908662: Preclinical and early clinical experience in combination with CTLA-4 blockade.
Authors: Callahan Margaret , Masters Gregg , Katz Jessica , Russell Valerie , Roman Ruth Ann , Montefusco Mary , Vyas Shachi , Yuan Jianda , Merghoub Taha , Gupta Ashok Kumar , Wigginton Jon , Jure-Kunkel Maria , Wolchok Jedd D.
Published: March 2020

2521

Background: Two new approaches to treat advanced melanoma have transformed the standard of care: the CTLA-4 blocking antibody, ipilimumab, and the targeted inhibitor of mutated BRAF, vemurafenib. These agents are mechanistically unique and combination therapy is a promising next step. We evaluated the combination of BMS908662 (662), a pan RAF inhibitor, with CTLA-4 blockade in preclinical studies and report first-in-human clinical experience with this combination. Methods: 1) We tested the impact of 662 on T cells in vitro, using cultured human T cells, and in vivo, using OT-1 transgenic mice. T cell activation and MAPK pathway signaling were assessed in parallel. 2) Preclinical studies measuring the anti-tumor activity of combination therapy were performed in CT-26 and SA1N tumor models. 3) Three pts with BRAF mutant stage IV melanoma were treated at MSKCC on CA206005, an IRB-approved protocol, receiving ipilimumab (3 mg/kg) and 662 (25 mg bid) (NCT01245556). Two pts consented to an IRB-approved protocol permitting immune monitoring. Results: 1) In vitro studies demonstrate that 662 can potentiate T cell activation after stimulation. This corresponds with increased MAPK pathway signaling, consistent with paradoxical activation of the MAPK pathway in wild type cells, a class effect of RAF inhibitors. In vivo, enhanced expansion of OT-1 cells after ovalbumin challenge was seen in mice treated with 662. T cell expansion was greatest in mice treated with a combination of CTLA-4 blockade and 662 (p<0.05). 2) Both preclinical models demonstrate superior anti-tumor activity with combination therapy compared to monotherapy (p<0.05). 3) All pts treated on protocol CA206005 tolerated combination therapy. New keratoacanthomas and SCCs, likely related to 662, were identified. One pt has an ongoing response at 10 mos (-85%), one had stable disease for 24 wks (-19%) and a third had disease progression. Enhanced MAPK signaling in PBMCs after treatment with 662 was detected ex vivo. Conclusions: RAF inhibitors may potentiate T cell activation in vitro and in vivo, offering one explanation for the enhanced anti-tumor activity seen in combination with CTLA-4 blockade in pre-clinical models.
Safety and long-term maintenance of anti-HER2 immunity following booster inoculations of the E75 breast cancer vaccine.
Authors: Dabney Raetasha Sheavette , Hale Diane F , Vreeland Timothy J , Clifton Guy T. , Sears Alan K. , Patil Ritesh , Ponniah Sathibalan , Shumway Nathan M. , Peoples George Earl , Mittendorf Elizabeth Ann
Published: March 2020

2529

Background: We have completed accrual and are in the follow up portion of phase I/II clinical trials evaluating the E75 HER2 peptide vaccine. E75 has been proven safe, capable of stimulating HER2 immunity, and effective in decreasing breast cancer recurrence rates. During the conduct of this trial, it was noted that E75-specific immunity waned after the Primary Vaccine Series (PVS) which corresponded with late recurrences. To maintain long-term immunity, a voluntary booster program was started. Here we present analysis of the booster inoculations. Methods: The trial enrolled node-positive or high-risk, node-negative breast cancer patients (pts) with tumors expressing any level of HER2 (IHC 1-3+). HLA-A2/A3+ pts comprised the vaccine group (VG), HLA-A2/A3- pts were followed as the control group (CG). The VG received 4-6 monthly inoculations of E75+GM-CSF. Volunteer booster program pts (BG) received inoculations every 6 months after the PVS. Pts were monitored for toxicities, in vivo responses by local reactions (LR) and DTH, and in vitro responses measured by enumeration of E75 specific cytotoxic T lymphocytes. Results: 53 pts received at least 1 booster, 34 received 2, 24 three, 20 four, 12 five, and 8 at least 6. 24% of pts had no local toxicity, 73% Grade 1 (G1), 3% G2. 74% had no systemic toxicity, 35% G1, 1% G2. LRs increased significantly from the initial vaccine (R1) during PVS to each booster (B) (R1: 59.5±3.1 v B1: 89.2±3.3, p<0.001; v B2: 95.15±5, p<0.001; v B3: 86.63±5.5, p<0.001; v B4: 83.26±4.6, p=<0.001; v B5: 80.67±6.7, p=0.006; v B6: 78.75±9.4, p=0.04). Dimer values increased from the end of PVS to each post-booster value (pre B1:1.29±0.25 v post B1: 1.46±0.38; post B2: 1.41±0.4; post B3: 1.84±0.35; post B4: 2.23±0.4; post B5:1.94±0.31; post B6: 2.73±0.09, p=0.02). At median 60 months, the recurrence rate for BG was 3.8% vs 18.9% in the CG (p=0.01). Conclusions: Booster inoculations are well-tolerated and appear to assist in the maintenance of long term peptide-specific immunity. Boosted pts have improved recurrence rates. Based on the success of this program, we have incorporated the practice of booster inoculations in our current cancer vaccine trials.
Pharmacological interactions of TKIs with the P-gp drug transport protein.
Authors: Roche Sandra , Pedersen Kasper , Dunne Grainne , Collins Denis , Devery Aoife , Crown John , Clynes Martin , O'Connor Robert
Published: March 2020

2536

Background: Tyrosine Kinase Inhibitors (TKIs) can interact with drug transport proteins. P-gp is a transporter with two important roles in cancer drug therapy. If overexpressed in tumour cells it can cause drug resistance. However, P-gp, expressed in tissues as part of normal drug clearance mechanisms, is also involved in termination of drug action. Hence, TKI-mediated interactions with P-gp have significant therapeutic consequences. Methods: P-gp over-expressing cancer cell lines were used to determine the inhibitor or substrate status of tyrosine kinase inhibitors (erlotinib, gefitinib, lapatinib, dasatinb, neratinib, afatinib and pazopanib). Cell proliferation assays in combination with a potent P-gp inhibitor, or P-gp substrate were also employed. Findings were augmented using LC-MS-based quantitation of cellular levels of target drugs. Results: We summarise our findings of four distinct interactions with P-gp among various TKIs. Some agents have little interaction at conventional doses; others can act as P-gp inhibitors without being substrates; substrates without being inhibitors or substrates which also prevent the actions of the transporter.Eachof the investigated TKIs has a distinct relationship with P-gp. As examples, lapatinib is an inhibitor but not a substrate, dasatinib is a substrate but not an inhibitor, while pazopanib has little interaction with P-gp. Other agents also have an effect on or are affected by P-gp to varying amounts with some of these interactions likely to be suprapharmacological. Conclusions: P-gp protein has important roles both in resistance and drug toxicology, hence, a clear understanding of the interaction of emerging drugs with this transporter is vital. Agents which are inhibitors of P-gp may have applications in drug resistance circumvention but may also greatly exacerbate the toxicity of concurrently administered P-gp substrate cytotoxics; conversely the activity of P-gp substrate TKIs may be reduced by tumour overexpression of the transporter. Hence in vitro screening of TKI-transporter interactions may identify putative TKI resistance mechanisms, help guide the development of combination schedule trials and/or reducing unwanted treatment side effects.
Pharmacogenetic study in metastatic colorectal cancer (CRC) patients receiving third-line panitumumab-irinotecan: A GERCOR ancillary study.
Authors: Etienne-Grimaldi Marie-Christine , Llorca Laurence , Formento Patricia , Chibaudel Benoist , Tournigand Christophe , Mabro May , Bachet Jean-Baptiste , Blons Helene , Laurent-Puig Pierre , Formento Jean-Louis , De Gramont Aimery , Andre Thierry , Milano Gerard A.
Published: March 2020

2537^

Background: Test the predictive value of gene polymorphisms potentially linked to panitumumab and irinotecan pharmacodynamics. Methods: 45 patients with metastatic CRC refractory to standard therapy were enrolled in this ancillary pharmacogenetic study as part of a phase II trial that included 63 patients. Inclusion required wild-type KRAS tumor status (codons 12-13, analyses performed in each center). After inclusion, central KRAS re-assessment was performed (codons 12-13-59-61) and 9 patients over 45 were found to carry a KRAS mutation. Patients received panitumumab (6 mg/kg, day 1) associated with irinotecan (180 mg/m2, day 1), Q2W until disease progression or unacceptable toxicity. Analyzed polymorphisms on blood DNA were : EGFR (CA repeats in intron 1, -216G>T, -191C>A), EGF (61A>G), CCND1 (870A>G), UGT1A1 (*28). Results: Cutaneous toxicity imputable to panitumumab i.e. folliculitis and paronychia was not linked to EGFR, EGF or CCND1 polymorphisms. Diarrhea (12 grade 1, 13 grade 2, 8 grade 3) was linked to CCND1 polymorphism: 22% grade 2-3 in AA patients vs 63% in AG+GG patients (p = 0.007). As expected, neutropenia (6 grade 1, 4 grade 2, 5 grade 3) was more frequent in patients bearing the *28 allele of UGT1A1 gene (33% grade 2-3 vs 5% in *1/*1, p = 0.020). In these 45 patients, response rate, progression-free survival and overall survival (OS) were only significantly related to re-assessed KRAS status. Of note, a tendency for a longer OS was observed in patients bearing the *28 allele of UGT1A1 gene (p = 0.091, analysis adjusted for KRAS). Interestingly, the frequency of KRAS mutation was higher in patients with long CA repeats in EGFR gene intron 1: 54.5% i.e. 6 mutated patients among the 11 patients with both alleles ≥17 vs 10.5% i.e. 2 mutated patients among the 19 patients with intermediary alleles vs. 6.7% i.e. 1 mutated patient among the 15 patients with both alleles <17 (p = 0.004). Conclusions: Present data indicate that A870 allele of CCND1 gene (40% AA patients) may protect from diarrhea induced by panitumumab-irinotecan. Also, these results report an original relationship between EGFR polymorphism in intron 1 and KRAS mutation status that merits further confirmation.
Relationship of variability in tumor measurement and response assessment.
Authors: Zhao Binsheng , Lee Shing Mirn , Lee Hyun-Ju , Qi Jing , Persigehl Thorsten , Tan Yongqiang , Schwartz Lawrence H.
Published: March 2020

2541

Background: RECIST is widely used to evaluate anti-cancer therapy efficacy. This study explored variability in reporting tumor change and response to therapy due to both target lesion selection and measurement. Methods: 2256 measurements were performed in CT scans of chest, abdomen and pelvis from 30 patients retrospectively taken from a multicenter Phase II/III colorectal clinical trial. Using RECIST, three radiologists interpreted baseline, 6-wk and 12-wk scans in the following manner: (1) Radiologists independently selected and measured target lesions, (2) one radiologist’s target lesions were re-measured by the other two and (3) one radiologist re-measured the same scans in the above manner at an interval of greater than a month to prevent memory recall. Measurement variability in total tumor burden (TTB) on relative changes at 6-wk and 12-wk from baseline was analyzed for inter- and intra-reader target lesion selection, inter- and intra-reader measurement using Bland-Altman method, and agreements on RECIST categorical responses were assessed by kappa coefficient. Results: When the same target lesions were used, inter- and intra-reader variability in TTB on relative changes at 6-wk and 12-wk from baseline were similar; all had 95% limits of agreement within (-15%, 15%). Kappa coefficients for RECIST were 0.74 (6-wk) and 0.87 (12-wk) for inter-reader and 0.64 (6-wk) and 0.88 (12-wk) for intra-reader to report responses. When radiologists independently selected and measured target lesions, variability in relative changes was within (-17%, 16%) at 6-wk and (-24%, 23%) at 12-wk for inter-reader and (-16%, 16%) at 6-wk and (-14%, 18%) at 12-wk for intra-reader interpretations. Kappa coefficients were 0.66 (6-wk) and 0.75 (12-wk) for inter-reader and 0.63 (6-wk) and 0.80 (12-wk) for intra-reader to report responses. Conclusions: Differences exist in measuring tumor change. The magnitude of change in categorical RECIST response is quantifiable. The largest differences are when radiologists independently select and measure target lesions, the smallest when one radiologist repeats measurements on identical target lesions. The variability may impact the reporting of categorical responses and trial results, especially in a single arm study.
A phase Ib dose-escalation study of eribulin mesylate in combination with capecitabine in patients with advanced/metastatic cancer.
Authors: Nasim Muhammad Yaser , Plummer Ruth , Evans T.R. Jeffry , Morrison Rosemary , Anthoney David Alan , Haney Sophie , Madi Ayman , Savulsky Claudio Isaac , Johnston Claire , Carter David , Reyderman Larisa , Gopalakrishna Prashanth , Wanders Jantien , Twelves Christopher
Published: March 2020

2552

Background: Eribulin mesylate is a microtubule dynamics inhibitor approved by FDA for patients (pts) with metastatic breast cancer after treatment with at least two prior chemotherapeutic regimens. This Phase Ib, open-label dose-escalation study determined the maximum tolerated dose (MTD) of eribulin in combination with capecitabine. Methods: Pts with advanced solid malignancies refractory to standard therapies, adequate organ function and ECOG performance status ≤2 received eribulin mesylate (2–5-min IV) by Schedule 1 (1.2, 1.6 or 2.0 mg/m2 on Day 1) or Schedule 2 (0.7, 1.1 or 1.4 mg/m2 on Days 1 and 8), in combination with twice-daily oral capecitabine 1000 mg/m2 Days 1-14 every 21 days. The MTD was defined as the highest dose in each schedule where ≤1/6 pts experienced dose-limiting toxicity (DLT). Safety and pharmacokinetics (PK) were assessed. Results: Of the 34 pts recruited, 19 (53% male; median age 62 years; 42% ECOG 0, 58% ECOG 1) and 15 (33% male; median age 61 years; 33% ECOG 0, 60% ECOG 1, 7% ECOG 2) were enrolled in Schedules 1 and 2, respectively. Most common tumor types were large intestine (20.6%), lung/bronchus (17.7%) and breast (14.7%). DLTs are shown in the table; there were no unexpected toxicities with the combination. The MTD for eribulin mesylate was 1.6 and 1.4 mg/m2 for Schedules 1 and 2, respectively, in combination with capecitabine 1000 mg/m2 twice-daily. Eribulin PK were dose proportional and independent of schedule or capecitabine co-administration. Combination with eribulin had no effect on the disposition of capecitabine and its metabolites. Although sample size was small, preliminary signs of efficacy were observed. Conclusions: The combination of eribulin and capecitabine was well tolerated with no unexpected safety findings. Schedule 2 MTD (1.4 mg/m2 Days 1 and 8) delivered a higher dose intensity of eribulin than Schedule 1 and was selected for evaluation in an ongoing Phase II breast cancer study. [Table: see text]
Phase I development of a weekly dosing schedule for the oral taxane tesetaxel.
Authors: Lang Amy , Beeram Muralidhar , Tolcher Anthony W. , Papadopoulos Kyriakos P. , Drengler Ronald , Smith Lon S. , Amaya Alex , Barnhurst Kelly , Itri Loretta , Patnaik Amita
Published: March 2020

2555

Background: Tesetaxel (TST) has anticancer activity in patients (pts) with metastatic breast cancer (MBC) and gastric cancer when administered orally once every 3 weeks (Q3W). This drug is not a Pgp substrate, does not cause hypersensitivity reactions, and may be associated with less neurotoxicity. The maximally tolerated dose (MTD) on the Q3W schedule is 27 mg/m2, and neutropenia is dose-limiting. Since taxane activity may be schedule-dependent, we conducted a weekly, dose-ranging, and PK evaluation of TST. Methods: Eligibility: advanced solid tumors; ECOG PS 0-2; adequate organ function. TST was given once weekly for 3 weeks in a 28-day cycle, beginning at a total flat dose of 25 mg/cycle with progressive increases in total dose up to 75 mg/cycle. Subsequently, dosing was converted to a weight-based regimen at weekly doses of 12.5, 15, and 17.5 mg/m2 (i.e., total per cycle dose up to 52.5 mg/m2). Serial plasma samples were assayed by HPLC. Results: 26 pts were treated in 8 dose cohorts. The MTD was 15 mg/m2/wk (total cycle dose, 45 mg/m2). With repeated cycles, constitutional symptoms (fatigue and anorexia) rather than neutropenia proved dose-limiting at 17.5 mg/m2/wk. Only 1 pt (at 12.5 mg/m2/wk) developed grade 3 neutropenia; no other episodes of Grade 3-4 myelotoxicity were observed. One pt with MBC (who had progressed after 2 prior taxane regimens) achieved a PR; 1 pt with prostate cancer has maintained prolonged reduction of PSA (> 57%). PK analyses showed low but progressive increases in trough TST concentrations (0.4–4.6 nmol/mL) 7 days after each succeeding dose, which was consistent with the prolonged T½ of this drug (~180 hrs). There was no substantial drug accumulation over multiple cycles. Conclusions: Weekly oral TST is safe, provides long-term low-level drug exposure, and increases the total delivered dose over 12 wks by 25%. Interestingly, this regimen is not associated with significant myelosuppression. Thus, weekly TST dosing provides a highly convenient, “dose-dense”, taxane regimen that is not associated with neutropenia, which should facilitate its integration into multiple chemotherapy regimens. An ongoing study is evaluating efficacy of weekly TST dosing in MBC.
Neoadjuvant sipuleucel-T in localized prostate cancer: Effects on immune cells within the prostate tumor microenvironment.
Authors: Fong Lawrence , Weinberg Vivian K. , Chan Stephen E , Corman John M , Amling Christopher L , Stephenson Robert A , Formaker Carl , Simko Jeffrey , Sims Robert Brownell , Carroll Peter , Small Eric Jay
Published: March 2020

2564

Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy for patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). To date, studies of sipuleucel-T in patients with mCRPC have studied immune response in peripheral blood. The effects of sipuleucel-T on prostate tumors are unknown. Methods: NeoACT (P07-1; NCT00715104) is an open-label, phase 2 study of patients with localized prostate cancer who received sipuleucel-T prior to radical prostatectomy (RP) to examine the immunologic effects of treatment on prostate tissue. Patients received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6-7 weeks prior to RP. The primary endpoint was the change in the frequency of lymphocytes between prostate biopsies (pre-treatment) and RP tissue (post-treatment), as assessed by immunohistochemistry (IHC). Results: The median age of the 42 enrolled patients was 61 years, and all had an ECOG performance status of 0. Thirty-eight patients received all 3 pre-RP sipuleucel-T infusions. To date, tissue IHC analysis has been completed on 32 patients. Treatment-related AEs were manageable and transient. Sipuleucel-T did not appear to impact surgery, as judged by operative complications, procedure time, and estimated blood loss. Frequent events that occurred ≤1 day after infusion (>10% of patients) were fatigue, headache, and myalgia. Significant increases (≥3 fold) in CD3+ and CD4+ T cell populations were observed at the tumor interface (where benign and malignant glands interface), compared with the pre-treatment biopsy, benign RP tissue, and tumor RP tissue (ANOVA post hoc Newman-Keuls test: p<0.0001 for each comparison). FoxP3+ CD4+ T cells were also increased (p=0.0005) at the tumor interface, but represented a small fraction of the observed CD4+ T cells. Conclusions: Neoadjuvant sipuleucel-T treatment is associated with an increased frequency of T cells in prostate cancer tissue at the interface of the benign and malignant glands. These data suggest that sipuleucel-T can modulate the presence of lymphocytes at the prostate tumor site. Work is ongoing to more fully characterize the immune response.
Targeting hyaluronan (HA) in tumor stroma: A phase I study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of pegylated hyaluronidase (PEGPH20) in patients with solid tumors.
Authors: Borad Mitesh J. , Ramanathan Ramesh K. , Bessudo Alberto , LoRusso Patricia , Shepard Harold Michael , Maneval Daniel C. , Jiang Ping , Zhu Joy , Frost Gregory I , Infante Jeffrey R.
Published: March 2020

2579

Background: HA, a glycosaminoglycan, accumulates in ~25% of solid tumors and is associated with poor prognosis. Tumors that accumulate HA develop high interstitial fluid pressure (IFP) and become resistant to chemotherapy. In animal models, PEGPH20 reduced tumor-associated HA and increased efficacy of chemotherapy. Methods: This ongoing phase 1 study was designed to assess safety, tolerability, PK, PD, and the maximum tolerated dose (MTD) of PEGPH20 as a single agent in patients with treatment-refractory solid tumors. IV PEGPH20 was administered in a twice weekly or a once weekly dosing schedule with oral dexamethasone (dex) pre-and post dose. Biomarkers included tumor histochemistry to detect HA depletion, plasma HA catabolites, and DCE-MRI or FDG-PET. Results: Fifteen patients have been enrolled into the study. Dose administration ranged from 0.5 µg/kg to 5 µg/kg. Musculoskeletal events (MSEs) were the most common and dose limiting toxicities. To date, up to 3 µg/kg twice weekly IV infusions of PEGPH20 were well tolerated with manageable Grade 1 MSEs in most patients. MTD has not been reached. Plasma concentrations of PEGPH20 showed dose proportional exposure with a terminal half life of ~2 days. Enzymatic activity of PEGPH20 was reflected by dose-dependent HA catabolites in plasma. Pre- and post-dose tumor biopsies from 2 colon patients demonstrated 23-60% reduction in tumor HA after 4 weeks of dosing. Serial DCE-MRI and FDG-PET demonstrated increased tumor perfusion (Ktrans) and decreased metabolic activity 8 and 24hrs post-PEGPH20 in one patient each. Doses of ≤3 µg/kg were tolerated with intermittent Grade 1-2 MSE. Enrollment at dose levels > 3 µg/kg is ongoing. Conclusions: Repeated IV PEGPH20 infusion resulted in dose-dependent systemic exposure and is tolerated with concomitant dex treatment. HA catabolites in plasma demonstrated the in vivo enzymatic activity of PEGPH20. Reduced HA in tumor biopsies and serial DCE-MRI and FDG-PET images confirmed PD activity. Increased tumor perfusion by PEGPH20 may enhance drug delivery to tumor. Combination studies of PEGPH20 with cytotoxic chemotherapy are planned.
Phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) trial of NGR-hTNF given at high doses in patients with refractory solid tumors.
Authors: Zucali Paolo Andrea , Simonelli Matteo , De Vincenzo Fabio , Lorenzi Elena , Perrino Matteo , Bertossi Monica , Balzarini Luca , Bonifacio Cristina , Lambiase Antonio , Bordignon Claudio , Santoro Armando
Published: March 2020

2580

Background: NGR-hTNF exploits the asparagine-glycine-arginine (NGR) peptide for selectively targeting tumor necrosis factor (TNF) to a CD13 overexpressed by tumor vasculature. Maximum tolerated dose (MTD) of NGR-hTNF was previously established at 45 µg/m2, when given as 1-h infusion every 3 weeks (q3w), with dose limiting toxicities (DLT) being grade 3 infusion-related reactions (IRRs). We explored further dose escalation by prolonging infusion time (2-h) and using premedication (paracetamol). Methods: DLTs were defined as drug-related grade 3/4 adverse events (AEs). PK and soluble TNF receptors (sR1-sR2) were tested in 46 pts. The volume transfer coefficient (Ktrans) and initial area under gadolinium concentration (IAUGC) were assessed before and 2 hours after dosing by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in 37 pts. Results: 12 dose levels (DLs) from 60 to 325 μg/m² q3w were evaluated. 48 pts (PS 0/1: 21/27; M/F: 37/11; median age: 61 years) received a total of 117 cycles (range 1-6). Prior regimens ranged from 1 to 7 (median 3). No DLT occurred and MTD was not reached. Study-emergent grade 3 and 4 AEs were reported in 12 (25%) and 5 (10%) pts, respectively. Grade 1/2 IRRs included chills (58%) and pyrexia (56%). Both Cmax (p<.0001) and AUC (p=.0001) increased with dose. Post-treatment peaks of sR2 were higher than sR1 (9.6 v 4.9 ng/mL; p<.0001). However, changes in sRs did not differ across DLs, with a plateau in shedding kinetics. By DCE-MRI assessment, median pre- and post-first cycle values declined from 0.15 to 0.09 min-1 for Ktrans (p=.02) and from 10.2 to 7.2 mM/L/sec for IAUGC (p =.0005). Over treatment, 28 pts (76%) showed decreases in IAUGC (-47%, p<.0001) and Ktrans (-59%; p<.0001) that were inversely correlated with baseline Ktrans values (p<.0001) and NGR-hTNF Cmax (p=.03). Of 41 evaluable pts, 12 (29%) had stable disease for a median time of 2.9 months. Survival at 1 year was 34%, with improved survival observed in pts with lower sTNF-R2 levels (p=.01) and greater Ktrans reductions (p=.05) after 1st cycle. Conclusions: NGR-hTNF can be safely escalated at doses higher than MTD and induces low shedding of receptors and early antivascular effects.
A phase II, single arm clinical trial involving an alternative cancer treatment psorinum therapy in patients with unresectable metastatic colorectal carcinoma.
Authors: Chatterjee Aradeep , Chakraborty Amitava , Bhattacharya Sudin , Bhakta Radhe S. , Chatterjee Ashim Kumar , Biswas Jaydip
Published: March 2020

2581

Background: We prospectively studied the clinical efficacy of an alternative cancer treatment “psorinum therapy” in treating unresectable metastatic colorectal carcinoma (UMCRC). Methods: Our study was phase-II, open level, single arm and single stage. Participants eligibility criteria included (1) histopathology confirmation of the malignancy (2) metastatic and unresectable disease status (3) No prior conventional cancer treatments (4) Karnofsky performance status between 40 – 70%. The primary outcome measures of the study were (1) to assess the radiological tumor response rate (using CT scanning procedure and following the RECIST criteria); (2) to assess how many participants survived at least 1 yr, 2 yrs, 3 yrs, 4 yrs and finally, after 5 yrs of the study. The secondary outcome measure was to assess the side effects of the investigational anti- cancer drug (psorinum) if any. Psorinum (an alcoholic extract of scabies slough and pus cells) was administered orally at a dose of 0.02ml / kg body weight / day as a single dose on an empty stomach for a complete course duration of 2 yrs to all the participants along with allopathic and homeopathic supportive cares. Results: 105 participants included in the final analysis at the end of the study. According to the RECIST criteria, complete response occurred in 12 (11.43%) cases and partial response occurred in 38 (36.19%) cases. 76 (72.38%) of them survived at least 1 yr, 58 (55.24%) survived at least 2 yrs, 51 (48.57%) survived at least 3 yrs, 43 (40.95%) survived at least 4 yrs and 37 (35.24%) of them survived at least 5 yrs. These participants didn’t receive conventional or any other investigational cancer treatments. Conclusions: The results of the study show clinical efficacy of psorinum therapy in treating patients with UMCRC. The investigational drug psorinum is non- toxic. Randomized controlled clinical trial should be conducted for further investigation of this alternative cancer treatment in treating unresectable metastatic colorectal carcinoma to integrate it into the mainstream of oncology treatments.
Phase I/II, two-part, open-label, multiple-dose, dose-escalation study of siltuximab in patients with solid tumors.
Authors: Angevin Eric , Elez Elena , Cohen Steven J. , Van Laethem Jean-Luc , Ottensmeier Christian , Joly Florence , Ray-Coquard Isabelle , Lopez-Martin Jose A. , Dirix Luc , Machiels Jean-Pascal , Clive Sally , Steven Neil Matthew , Reddy Manjula , Hall Brett , Puchalski Thomas , Bandekar Rajesh , Van De Velde Helgi , Tromp Brenda J. , Vermeulen Jessica , Kurzrock Razelle
Published: March 2020

2583

Background: Siltuximab (S) is a chimeric mAb with high affinity for soluble IL-6. This Ph 1/2 study evaluated safety, efficacy and PK of escalating, multiple IV doses of S from a new cell line in patients (pts) with advanced refractory solid tumors. Methods: In Ph 1, S was given to 20 pts with advanced solid tumors at escalating dose levels (2.8 or 5.5 mg/kg q2w or 11 or 15 mg/kg q3w) and to 24 pts with taxane and platinum resistant ovarian cancer (OVC) or KRAS mutant (KRASmt) tumors at 15 mg/kg q3w. In Ph 2, 17 OVC pts and 23 KRASmt pts received the Ph 1 selected dose of 15 mg/kg q3w. The Ph 2 primary efficacy endpoint was clinical benefit rate (CBR: CR + PR + SD of > 6 wk). Results: In Ph 1-2, 84 pts (35 colorectal, 29 OVC, 9 pancreatic, 11 other) pretreated with a median of 4 prior tx regimens received a median of 3 (range 1, 45) cycles. 1 DLT occurred at 5.5 mg/kg; MTD was not reached. 62% pts had AEs gr ≥ 3 in Ph 1-2, most common were hepatic function abnormalities (15%), PS deterioration (12%), fatigue (11%). 10% pts had possibly S-related AEs gr ≥ 3; only neutropenia (4%) was reported in >1 pt. 42% pts had SAEs, most were related to underlying disease, 2% were possibly S-related. 18 deaths occurred on study, 17 due to PD, 1 due to AE. No pt had antibodies to S. The PK profile was bi-exponential with a t1/2 ranging 15 − 20 d. PK profile of S from the new Chinese hamster ovary cell line appears similar to the previous murine Sp2/0 myeloma cell line. CBR in Ph 2 was 5%. ORR by RECIST was 26% SD in Ph 1, 9% SD in Ph 2. 1 OVC pt had CA 125 response. In Ph 2 the median PFS was ~ 2 mo in both cohorts; the median OS was 4.2 mo in KRAMSmt and 11 mo in OVC. Hb increased by a max of ≥10 g/L in 73% pts given 15 mg/kg in Ph 2, with 94% showing a median decrease of 68% at d 8 after dose 1 in hepcidin, a regulator of iron homeostasis. CRP was suppressed in all pts during tx, with median decrease 93% at 11 mg/kg and 88 − 93% at 15 mg/kg as early as d 8 after dose 1. Other biomarkers will be presented. Conclusions: S appears to be well tolerated; doses of 11 − 15 mg/kg q3-4w can be used in future studies. No CR/PR was observed, although some pts with advanced solid tumors had durable SD and CRP suppression. Improvement in Hb was observed in a large proportion of pts, indicating a role of IL-6 in anemia that needs to be further explored.
Effect of the novel therapeutic cancer vaccine formulation DPX-0907 on multifunctional T-cell responses in ovarian, breast, and prostate cancer patients.
Authors: Berinstein Neil Lorne , Karkada Mohan , Nigam Rita , Morse Michael , Nemunaitis John J. , Chatta Gurkamal S. , Kaufman Howard , Odunsi Kunle , Weir Genevieve , MacDonald Lisa , Stanford Marianne , Mansour Marc
Published: March 2020

2588

Background: To increase the efficacy of peptide cancer vaccines, we developed a novel vaccine platform called DepoVax, an adjuvanted water-free depot formulation with the ability to generate enhanced immune responses. Naturally processed HLA-A2 restricted peptides that are selectively presented by breast, ovarian and prostate cancer cell lines, but not by normal HLA-A2+ cells, were used as antigens with a proprietary adjuvant and a T helper peptide epitope to create a therapeutic cancer vaccine, DPX-0907. Methods: A phase I clinical study was designed to examine the safety and immune activating potential of DPX-0907 in advanced stage breast, ovarian and prostate cancer patients. A total of 23 late stage cancer patients were recruited and were divided into two dose volume cohorts in a three immunization clinical protocol. Results: DPX-0907 proved to be safe with no serious adverse effects related to the vaccine reported. Of those evaluable for immunogenicity, all breast cancer patients (3/3), most of ovarian (5/6) and one third of prostate (3/9) cancer patients demonstrated immune response to one or more of seven antigenic peptides, resulting in a 61% response rate. Immune responses correlated with achievement of CR, PR or SD to last treatment. No difference in immune response rate or magnitude was seen between the two dose groups. DPX-0907 displayed strong immune induction potential, with 73% of immune responders showing responses with just one dose of vaccine. In 83% of responders, immune responses were detected at ≥2 time points post vaccination and 64% had a persistent immune response at one month post last vaccination. Immune monitoring showed peptide-specific CD8 T cells, and these T cells were able to secrete multiple Th1 cytokines indicating their multifunctionality, a feature attributable to cells that mediate protective responses. Conclusions: These data support the ability of DPX-0907 to elicit Th1 dominated, specific immunity and support the rationale for further testing in immunologically competent cancer patients. The novel DepoVax formulation may promote multifunctional memory responses with peptides from other tumor associated antigens.
A phase I study of lapatinib (LPT) and cetuximab (CTX) in patients with CTX-sensitive solid tumors.
Authors: Deeken John F. , Wang Hongkun , Hwang Jimmy J. , Marshall John , Subramaniam Deepa Suresh , He Aiwu Ruth , Weiner Louis M. , Hardesty Rosemarie A. , Steadman Kenneth , Pishvaian Michael J.
Published: March 2020

2590

Background: Preclinical research has shown that one mechanism of acquired resistance to CTX is via EGFR-ErbB2 heterodimerization, which can reactivate oncogenic pathways. LPT is a dual EGFR and ErbB2 intracellular tyrosine kinase inhibitor. A phase I translational clinical study was performed to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and clinical activity of CTX and LPT in patients with EGFR-driven solid tumor malignancies that can be treated with CTX. Methods: Patients (Pts) were enrolled in a 3+3 dose escalation trial. Prior CTX therapy was allowed. CTX was given at 400mg/m2 on Cycle 1, Day 1 (C1D1), then 250 mg/m2 weekly. LPT dose levels (DL) were (1) 750mg, (2) 1000mg, and (3) 1250mg orally daily. Rash management included daily sunblock, steroid cream, and doxycycline. Cycle length was 21 days, and patients were assessed for toxicity through the end of C2, and for efficacy after every 2 cycles. Fresh tumor biopsies were obtained at baseline and at the end of C1 to compare EGFR and ErbB2 expression levels and EGFR related pathway activation. DNA from blood samples was analyzed for pharmacogenetic (PGx) variations and correlations with toxicity and pharmacokinetics (PK). Results: Between October, 2010 to January 2012, 13 pts were enrolled, with colon (4), lung (3), head and neck (3), and anal cancers (3); 10 were evaluable for toxicity. Treatment-related toxicities of any grade included: rash (67%), diarrhea (42%), fatigue (33%), nausea/vomiting (17%), and dehydration (8%). DLTs included G3 rash in 1 of 6 pts on DL1, and G3 diarrhea despite optimal therapy in 1 of 4 pts on DL2. Enrollment to DL2 continues. Of 7 pts evaluable for response, 1 had an uPR, 3 had SD, including 1 with SD of ≥4 cycles, and 3 had DP. Both patients with uPR and prolonged SD were treated on DL1. Tumor EGFR-ErbB2 and EGFR pathway phosphorylation analyses and PGx results will be presented. Conclusions: The combination of CTX and LPT is well tolerated with expected toxicities. Efficacy was seen even on DL 1. Phase II clinical studies in CTX-sensitive diseases such as colon and head and neck cancer are planned.