bluuebunny/crossref_metadata_2025 huggingface dataset:
Dosing of troxacitabine (Troxatyl [T], SGX-145) based on renal function
Authors: Kelner M. J. , Giles F. J. , Feldman E. J. , Roboz G. J. , Deangelo D. J. , Burley S. K.
Published: March 2020

2025

Background: Troxacitabine (Troxatyl [T], SGX-145) is a novel L-configuration nucleoside analog anti-cancer agent with unique mechanistic/cytotoxic properties. T is clinically active against acute myelogenous leukemia (AML), chronic myeloid leukemia, myelodysplastic syndromes (MDS), renal cell carcinoma, and pancreatic cancer. A multi-center Phase 2/3 clinical trial is currently underway to evaluate the safety and efficacy of continuous IV infusion T treatment in second salvage AML. The major route of elimination of troxacitabine is renal excretion as unchanged drug (∼70%) and there is minimal protein binding. These results suggest that renal function may have a significant effect on steady-state troxacitabine plasma concentrations (Css). Methods: Pharmacokinetic and toxicity data from four AML clinical trials (>200 patients) are being analyzed to (1) Identify a minimum Css for therapeutic efficacy; (2) Define an upper limit of Css for adverse risk; and (3) Develop a mechanism to prospectively modify the troxacitabine dose based on renal function, which would avoid excessive toxicity while maintaining therapeutic blood levels. Results: Initial results from 41 patients indicate that to induce remission in AML patients, troxacitabine steady-state plasma concentrations (Css) must be ≥ 80 ng/mL. However, higher Css values correlate with increased toxicity and, thereby, increase the risks of the treatment for an individual patient, although an upper limit for adverse risk has not yet been defined. For patients with normal renal function (creatinine clearance ≥ 50 but ≤ 125 mL/min), a Calvert style formula, based on a patient’s estimated creatinine clearance, has been developed to define the dose required to achieve a therapeutic Css ≥ 80 ng/mL. Both linear and non-linear nomogram models are also being developed to adjust troxacitabine dosage for patients with moderate renal impairment (30 mL/min < creatinine clearance < 50 mL/min) or for patients with high GFR (creatinine clearance > 125 mL/min). Conclusion: A firm relationship exists between renal function, troxacitabine clearance, and Css values. This result indicates that a dosing strategy based on renal function may be warranted to obtain optimal troxacitabine Css values.

[Table: see text]
A genomic strategy to combinatorial therapeutics in solid tumors
Authors: Potti A. , Dressman H. K. , Bild A. , Riedel R. , Kelley M. , Ginsburg G. , Lancaster J. , Nevins J. , Febbo P.
Published: March 2020

2031

Background: For most advanced solid tumors, the response rate to cytotoxic drugs is generally low, highlighting the importance of identifying those patients most likely to respond, either to single agents or combinations of cytotoxic or targeted therapies. Methods: We have made use of in vitro drug response data generated on the NCI-60 panel of cancer cell lines, coupled with Affymetrix U133 2.0 plus gene expression data, to develop genomic predictors of chemotherapy sensitivity. These models were then validated in independent cancer cell lines as well as response data from patient treatment studies. Results: Predictive models making use of gene expression data were developed for docetaxel, adriamycin, 5-flourouracil, cyclophosphamide, paclitaxel, and topotecan. These models were shown to accurately predict sensitivity to the drugs in an independent set (n = 30) of cancer cell lines. Importantly, three of the predictors (docetaxel, topotecan, paclitaxel) also accurately (> 80%) predicted response in patient studies. When evaluated in a large collection of human cancers (n = 381), these gene expression signatures of drug response identified patterns of predicted sensitivity suggesting potential opportunities for novel combinations. We also combined the predictions of chemotherapy sensitivity with predictions of pathway deregulation (Bild A, Nature 2005), to develop further opportunities for combination therapy. For instance, this analysis revealed a significant relationship between PI3 kinase pathway deregulation and docetaxel resistance (p = 0.001), and a correlation between docetaxel sensitivity and the activation of the Rb/E2F pathway (p = 0.009). Furthermore, cell lines showing an increased probability of PI3 kinase and Rb/E2F activation were also more likely to respond to a PI3 kinase (LY-294002) inhibitor (p = 0.01) or R-Roscovitine (p = 0.03), a cell cycle inhibitor, respectively. Conclusions: The development and validation of chemotherapeutic response predictors, together with oncogenic pathway signatures that can guide the use of targeted agents, provides an opportunity to develop effective combinatorial therapeutic strategies geared to the individual patient.

No significant financial relationships to disclose.
A phase I repeated dose escalation study of the Polo-like kinase 1 inhibitor BI 2536 in patients with advanced solid tumours
Authors: Hofheinz R. , Hochhaus A. , Al-Batran S. , Nanci A. , Reichardt V. , Trommeshauser D. , Hoffmann M. , Steegmaier M. , Munzert G. , Jäger E.
Published: March 2020

2038

Background: BI 2536 is a novel highly potent and selective inhibitor of the serine-threonine kinase polo-like kinase 1 (Plk1), which is a key regulator of cell cycle progression. Objectives of this trial were the assessment of the maximum tolerated dose (MTD), overall safety, pharmacokinetics and efficacy of BI 2536 given intravenously. Methods: Sequential cohorts of 3 to 6 patients (pts) with pretreated advanced or metastatic solid tumours received intravenous infusions of BI 2536 on days 1 and 8 of a 3-week treatment course following a toxicity guided dose escalation design. Further treatment courses were administered to pts in the absence of disease progression and if toxicity after a 3-week treatment course had resolved. Results: A total of 42 pts was treated at doses of 25 mg (n=3), 50 mg (n=3), 100 mg (n=22), 125 mg (n=5), 150 mg (n=6) and 200 mg (n=3). Reversible CTCAE grade ≥ 3 neutropenia in 14/42 pts represented the main drug related toxicity with an incidence of 3/5 in the 125 mg cohort, 4/6 in the 150 mg and 2/2 in the 200 mg dose cohorts. Dose limiting toxicity (DLT) was defined as drug related toxicity prohibiting administration of the day 8 dose of BI 2536 (hematologic: CTCAE ≥ 3 grade, non-hematologic toxicity: CTCAE ≥ 2). No DLT other than d8 neutropenia was observed. The MTD was defined at 100 mg for the given day 1 and 8 schedule. Further related adverse events (AE’s) were of mild to moderate intensity (CTCAE grade ≤ 2). There were no related AEs resulting in study discontinuation. Preliminary PK analysis showed dose proportionality of Cmax and AUC0-∞ with a high clearance (∼ 1500 mL/min) and a high volume of distribution (∼ 2000 L). No accumulation from d1 to d8 occurred. Patients were treated for up to 8 courses without evidence of accumulating toxicity. No objective responses were observed according to RECIST criteria in this heavily pretreated patient population. Conclusions: In summary BI 2536 is a Plk1 inhibitor with a favorable PK and safety profile at the tested dose and schedule. Neutropenia as a mechanism-related toxicity indicates target inhibition in vivo.

[Table: see text]
Population pharmacokinetic of total cisplatinum: Application to adaptative dosing with feed back in testicular cancer patient
Authors: Salas S. , Mercier C. , Ciccolini J. , Pourroy B. , Dupuis C. , Deville J. , Baciuchka-Palmaro M. , Durand A. , Duffaud F. , Tranchand B. , Favre R.
Published: March 2020

2043

Background: Cisplatinum (CDDP) is major drug used in germ cell testicular cancer. Pharmacokinetics (PK)/pharmacodynamics relationships have been described after measurement of free CDDP in plasma, and subsequently, CDDP administration is standardized using body surface area (BSA) for only dose tailoring. Methods: Based on a rapid assay of total CDDP in plasma we have developed an alternative 120-hours continuous infusion schedule, coupled to a Bayesian adaptive dosing strategy. We present a retrospective evaluation of this schedule in 19 patients (66 courses) treated for testicular germ cell tumors. A NONMEM analysis was then performed to identify the covariates associated with total CDDP clearance. We compared doses effectively given to our patients with the ones calculated with BSA. Results: Plasma samples were analyzed to allow real-time Bayesian estimation of individual PK parameters with subsequent daily dose adjustment in order to reach a target Cend of 1.95 mg/l of total platinum. No statistical difference was observed between experimental and target values, and Cend adjustment was achieved with an overall 6.6% precision, a performance to be compared with the 54% inter-patient variability observed in drug clearance. Course number (CNB) was the only covariate to be correlated with total CDDP clearance. A weaker correlation was found with BSA, and only when considering first courses. Moreover, doses of CDDP administered were significantly higher than the ones classically normalized with BSA, thus leading to an overall greater exposure in our patients. Only few severe toxicities were reported, and all of the patients presented in this study were still alive and disease-free after a follow up of up to 15 years. Conclusions: Our alternative schedule is a convenient and safe strategy to ensure administration of optimal dose-intensity of CDDP, with limited side-effects in patients with testicular cancer. We demonstrate a linear correlation between course number and decrease of CDDP clearance (25%). This, highlights the critical importance of total drug accumulation on CDDP PK when several infusions are to be administered in a row, and therefore the need for developing dynamic dose individualization strategies that includes CNB.

No significant financial relationships to disclose.
A phase I dose-escalation and pharmacokinetic study of enzastaurin combined with capecitabine in patients with advanced cancer
Authors: Leong S. , Camidge R. , Eckhardt G. , Basche M. , Musib L. , Darstein C. , Thornton D. , Britten C.
Published: March 2020

2048

Background: Enzastaurin (ENZ), an oral inhibitor of protein kinase C (PKC), affects signal transduction associated with angiogenesis, proliferation, and survival. The combination of ENZ and capecitabine (CAPE) has the potential for additive or synergistic anticancer effects without excessive toxicity. Methods: Patients (pts) with advanced, refractory, solid tumors received lead-in treatment with ENZ for 7–14 days (cycle 1), to achieve steady-state exposures. In subsequent 21-day cycles, ENZ was given once daily, orally, on days 1–21 and CAPE twice daily (bid), orally, on days 1–14 in 3 dose levels (L): L 1 = ENZ 350 mg + CAPE 750 mg/m2; L 2 = ENZ 350 mg + CAPE 1000 mg/m2; L 3 = ENZ 525 mg (some pts received 500 mg tablets) + CAPE 1000 mg/m2. PK for ENZ was assessed on day 1–3 and 7 in cycle 1 and day 8 in cycle 2 and for CAPE on day 1, 8 in cycle 2. Therapy continued until disease progression or unacceptable toxicity occurred. Results: 27 pts (13 males; 14 females, ECOG ≤1) with a median age of 58 yrs (range: 38–74 yrs), received a median number of 3 cycles (range: 2–14 cycles). High interpatient PK variability was noted for total ENZ analytes. Ratio of geometric mean AUC (90% CI) of ENZ with CAPE versus ENZ alone at 500/525 mg was 0.65 (0.38–1.11, n=6) and of Cmax was 0.66 (0.42–1.10, n=4). PK parameters of CAPE in the presence of ENZ were similar to those previously reported for CAPE alone. No grade (Gr) 4 toxicities occurred. Gr 3 toxicities were anemia (1 pt), headache (1 pt), intestinal perforation (1 pt with gastric carcinoma), fatigue (1 pt), hand-foot syndrome (2 pts), and cardiac ischemia (1 pt). PBMCs demonstrated PKC inhibition following exposure to ENZ. Plasma VEGF and bFGF levels did not reflect any significant changes. No objective tumor responses were seen. Five pts had stable disease (lung, breast, pancreas, head/neck, and hemangiopericytoma) for ≥ 6 months (range: 6–9.7 months). Conclusions: The recommended phase II dose is ENZ 500 mg, qd and Cape 1000 mg/m2 bid, days 1–14 every 21 days. This regimen was well tolerated, and exposures of ENZ and CAPE did not appear to be significantly altered when given in combination.

[Table: see text]
Dose dependent inhibition of uridine phosphorylase (UP) by eniluracil (EU): Was the clinical inferiority of the EU/5-fluorouracil (5-FU) phase III trials due to an unrecognized inhibition of 5-FU anabolism?
Authors: Fourie J. , Guarcello V. , Diasio R. B.
Published: March 2020

2058

Background: Eniluracil (EU) is an irreversible inactivator of dihydropyrimidine dehydrogenase (DPD). EU inhibits DPD dependent 5-fluorouracil (5-FU) catabolism, allowing for oral 5-FU administration with essentially complete bioavailability. Although earlier murine studies suggested an increased antitumor effect when EU was administered before 5-FU, clinical studies used co-administered EU and 5-FU (ratio: 10 EU:1 5-FU) (b.i.d.). These phase III trials demonstrated inferiority compared to a regimen of 5-FU/leukovorin, leading to discontinuation of EU development. We hypothesize that the clinical failure of this EU/5-FU schedule may have resulted from competitive inhibition of 5-FU anabolic (ANA) activation by EU. In this study we examined whether EU could competitively inhibit uridine phosphorylase (UP) or orotate phosphoribosyl transferase (OPRT), the primary ANA enzymes of 5-FU. Methods: The cytoplasmic fraction of human embryonic kidney cells (HEK-293) was used as the source of UP and OPRT. Reverse phase HPLC with radioactivity detection was used to quantify [2-14C]-uracil formation from [2-14C]-uridine (UP activity) and to quantify [6-14C]-FUMP formation from [6-14C]-5-FU (OPRT activity). For UP activity, reaction mixtures consisted of increasing concentrations of EU in phosphate buffer containing 150 μM [2-14C]-uridine. For OPRT activity, reaction mixtures consisted of increasing concentrations of EU in phosphate buffer containing 5 μM [6-14C]-FU and 100 μM benzylacyclouridine (UP inhibitor). Reactions were initiated with addition of UP/OPRT enzyme source and allowed to proceed for 30 min at 37°C. Results: EU displayed dose-dependent competitive inhibition of UP activity (IC50 = 0.375 mM). In particular, the EU/5-FU ratio of 2.5:1 produced approximately 50% inhibition of UP activity. In contrast, EU did not inhibit OPRT activity. Conclusions: This study demonstrates that EU competitively inhibits UP, an important enzyme in 5-FU ANA activation, and suggests that changing the dose ratio and/or increasing the interval between EU and 5-FU administration may be useful in optimizing 5-FU antitumor efficacy.

[Table: see text]
Pharmacological inhibition and silencing of classical IKK-NF-κB pathway by siRNA sensitizes cancer cells to doxorubicin
Authors: Tapia M. , Bosch M. , Rolfe M. , Ross J. S. , Gascón P. , Perona R. , Rovira A. , Albanell J.
Published: March 2020

2059

Background: The IKK/NF-κB pathway (IKK1, IKK2 and NEMO; p65, p50, p52, c-Rel, RelB) is involved in chemoresistance. NF-κB is activable by either a classical or an alternative Ipathway. Here we studied whether NF-κB inhibitors sensitized cells to doxorubicin (dox), and assessed the role of individual IKK or NF-κB subunits by RNA interference [ small interfering RNA (siRNA)] on doxorubicin sensitization. Methods: We used BT474 and MDA-MB453 cells (breast) and HeLa cells (cervix). NF-κB inhibitors were bortezomib (Velcade, a proteasome inhibitor, which inhibits NF-κB by promoting accumulation of the inhibitory Iκ B-α) and a NEMO-Binding-Peptide (NBP, which prevents IKK proteins from complexing). NF-κB DNA binding activity was measured by EMSA. Western blot was used to assess nuclear translocation of individual NF-κB subunits (Iκ B-α, p65, c-Rel, RelB, p50 and p52). BT474 and MDA-MB453 cells were cultured with dox with/without NF-κB inhibitors and viability was assayed by MTT. siRNA was used to transiently down-regulate subunits that act preferentially on the classical NF-κ B (p65, p52, c-Rel, or NEMO) or on the alternative pathway (RelB) in HeLa cells. Chemosensitivity of transfected and control cells to dox was measured by MTT. Results: Dox increased NF-κB activity in BT474 and HeLa cells, as assayed by EMSA and/or by showing Iκ B-α degradation and phosphorylation of p65. Pretreatment of BT474 cells with bortezomib followed by dox resulted in a 30% reduction in cell viability compared to dox alone. Moreover, a 40% higher dox sensitivity was observed when cells were pretreated with a NEMO-Binding-Peptide. Similar data were obtained in MDA-MB453 cells. Transient down-regulation of key members of the classical IKK- NF-κB pathway (p65, p52, c-Rel and NEMO) by siRNA in HeLa cells lead to a 30% increase in dox cytotoxicity. In contrast, silencing of RelB, a key subunit of the alternative pathway, had no effect on dox cytotoxicity under our assay conditions. Conclusions: NF-κB inhibition sensitized cells to dox, implying directly p65, p52, c-Rel and NEMO subunits in chemoresistance, but not RelB. These findings suggest that selective inhibition of the classical IKK-NF-κB pathway is sufficient to improve dox antitumor effects.

[Table: see text]
A three schedule phase I trial of CP-4055, weekly and q2 weeks in patients with advanced or metastatic solid tumors
Authors: Delaunoit T. , Raymond E. , Awada A. , Savinelli F. , Culine S. , Rasch W. , Yovine A. , Houédé N.
Published: March 2020

2067

Background: CP-4055 (ELACYT, ara-C 5’-elaidic acid ester) is a novel cytotoxic agent with broad preclinical antitumor activity in solid tumors. CP-4055 is based on Lipid Vector Technology and has a different cellular uptake compared to ara-C. An initial phase I trial of a day 1–5 q4 weeks (w) schedule (sch) determined a recommended dose of 200 mg/m2/day and showed clinical activity (Aamdal et al, AACR 2005). We report a multiple sch, parallel, dose intensity-guided dose escalation phase I trial, with pharmacokinetic (PK) assessment, intended to determine Maximum Tolerated Dose (MTD). Methods: Patients (pts) with refractory solid tumors received i.v. CP-4055 over 2 hours according to 3 sch: days 1, 8 q3w (Sch 1); days 1, 15 q4w (Sch 2); days 1, 8, 15 q4w (Sch 3). Dose escalation: dose level (DL) 1: 80 mg/m2/w, DL2: 160; DL3: 240; DL4: 320; DL5: 400; DL6: 440; DL7: 520, with standard definitions of dose limiting toxicity (DLT). Results: Since June 2004, 45 pts have been treated in 4 European centers; 3 are still ongoing, 37 discontinued for progressive disease, 3 for refusal, 2 for AE (1 treatment-related grade [gr] 3 paresthesia), trial is ongoing. Demographics: male/female: 27/18; median age 54 (range 35–79); ECOG PS 0/1/2: 19/24/2. Main tumor types: colorectal 6, breast 5, head & neck 5; median 3 lines prior chemotherapy (range 0–5). Exposure: 128 cycles administered, including 5 pts with ≥ 6 cycles. MTD: No DLT has been observed and dose escalation is ongoing. Safety (NCI-CTCAE v3): 45 pts assessable. Principal toxicities by pt (gr 1–2/3): anemia 34/1; nausea and vomiting 29/3; asthenia 24/1; neutropenia 12/2; headache 8/0; thrombocytopenia 3/0. No clear association with sch or DL was observed for this mild/moderate toxicity. There were no dose reductions. PK: ara-U/ara-C AUC ratio exceeds by 3-fold the standard ara-U/ara-C AUC ratio. Efficacy: 41 pts were assessable, 10 pts had stable disease (lasting > 6 months in 4 pts: 2 NSCLC, 1 colorectal, 1 kidney). Conclusions: CP-4055 shows preliminary evidence of activity and is well tolerated up to a dose of 440 mg/m2/w. PK results indicate that a majority of ara-U in plasma originates from intracellular deamination of ara-C from CP-4055, confirming intracellular retention of CP-4055. Accrual is ongoing at the DI of 520 mg/m2/w.

[Table: see text]
Phase I study of vorinostat, a histone deacetylase (HDAC) inhibitor, in combination with carboplatin (Cb) and paclitaxel (P) for patients with advanced solid malignancies (NCI #6922)
Authors: Ramalingam S. , Parise R. A. , Egorin M. J. , Argiris A. , Stoller R. , Beattie L. , Aparicio A. , Newman E. M. , Zwiebel J. , Belani C. P.
Published: March 2020

2077

Background: Vorinostat (SAHA) induces differentiation & growth arrest in a variety of human carcinoma cell lines by inhibiting HDAC. It also enhances the efficacy of chemotherapy. We are conducting a phase I study to evaluate the combination of vorinostat, Cb & P for patients with advanced solid malignancies. Methods: Patients with advanced solid malignancies who were candidates for combination therapy with Cb & P were eligible. Vorinostat was given orally on d 1–14 of each 21-d-cycle, except in cycle 1 when begun on d -4 to facilitate PK studies. Cb & P were given on d 1 of each cycle. Plasma concentrations of vorinostat, & its 2 major metabolites were quantitated with a novel LC-MS/MS assay. Results: Dose level 4 has been determined as the recommended phase II dose (RP2D) for the combination, since the RP2D of single agent vorinostat is 400 mg on this schedule. Observed toxicities included nausea, vomiting, neutropenia & thrombocytopenia, none of which were dose-limiting. Of 9 patients evaluable for response, 4 had PR (1 head & neck cancer, 3 non-small cell lung cancer), & 2 had stable disease. Vorinostat was rapidly absorbed & AUC increased with dose. Vorinostat PK parameters included Tmax 0.5–2 h, t1/2 1.6 ± 0.5 h, & CL/F 5.8 ± 1.7 l/min. Cb & P did not alter vorinostat PK. 4-Anilino-4-oxobutanoic acid was the major, & long-lived, vorinostat metabolite, with Cmax 1.5–7 fold > vorinostat Cmax & t ½ ∼6h. Vorinostat glucuronide Cmax was 1–5 fold > vorinostat Cmax & glucuronide t ½ ∼2h. The RP2D cohort is being expanded to 12 patients to obtain additional clinical & PK data. Conclusions: Vorinostat can be safely administered in combination with Cb & P at their recommended doses. Vorinostat PK are not altered by Cb & P. Promising anti-cancer activity has been noted in patients with advanced NSCLC. Support: U01CA099168–01, U01CA62505, NIH/NCCR/GCRC grant 5M01RR 00056.

[Table: see text]

No significant financial relationships to disclose.
Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody
Authors: Vonderheide R. H. , Flaherty K. T. , Khalil M. , Stumacher M. S. , Bajor D. L. , Gallagher M. , Sullivan P. , Mahaney J. J. , O’Dwyer P. J. , Huhn R. D. , Antonia S. J.
Published: March 2020

2507

Background: The cell-surface molecule CD40 plays a critical role in activating antigen presenting cells (APC) and mediates upregulation of costimulatory and MHC molecules, cytokine release, and enhancement of tumor immunity. CD40 is also expressed by 30%-70% of solid tumors, and engagement of CD40 on tumor cells results in apoptosis. CP-870,893 - a fully human and selective CD40 agonist monoclonal antibody - activates human APC in vitro and inhibits growth of human tumors in immune-deficient and immune-reconstituted SCID-beige mice. Methods: A phase 1, dose-escalation study of CP-870,893 was designed to characterize the safety and maximum tolerated dose (MTD) of single doses of CP-870,893 in patients (pts) with advanced solid tumors. CP-870,893 was administered i.v. on day 1 and pts were followed for 43 days. Results: Twenty-nine pts received CP-870,893 in doses ranging from 0.01 to 0.3 mg/kg. Dose limiting toxicity was observed in 2 of 7 pts at the 0.3 mg/kg dose level (venous thromboembolism and grade 3 headache). The MTD was defined as 0.2 mg/kg. The most common adverse event was dose-related cytokine release syndrome (grade 1 to 2). Abnormal lab findings included dose-related and transient elevations in liver transaminases (grade 1 to 2; one pt with grade 3). Modest elevations in serum D-dimer were observed in pts treated at the highest dose levels. Four pts with melanoma (14% of all pts and 27% of pts with melanoma) had objective partial responses (PR) at day 43 evaluation (one PR sustained at 7+ months and 3 unsustained on follow-up scans). Each pt with a PR received 0.2 or 0.3 mg/kg of antibody. To assess pharmacodynamic actions of CP-870,893, flow cytometry was performed on peripheral blood B cells, which uniformly express CD40. CP-870,893 infusion resulted in depletion of peripheral CD19+ B cells (>80% depletion at the highest dose levels). Among B cells remaining in blood, we found a marked, dose-related upregulation of costimulatory and MHC molecules after treatment. Conclusions: Clinical and laboratory findings demonstrate biological activity of CP-870,893. Antitumor activity was observed in 4 pts with melanoma. Further studies of repeated doses of CP-870,893, and CP-870,893 in combination with other antineoplastic agents, are warranted.

[Table: see text]
Therapeutic targeting of CD70 and CD27-CD70 interactions with the monoclonal antibody SGN-70 in Waldenstrom’s Macroglobulinemia (WM)
Authors: Ho A. W. , Hatjiharissi E. , Branagan A. , Hunter Z. , McEarchern J. , Law C. , Grewal I. S. , Santos D. , Tai Y. , Treon S. P.
Published: March 2020

2509

Background: WM represents a lymphoplasmacytic lymphoma characterized by a monoclonal IgM gammopathy and possesses a mast cell component that may contribute to its pathogenesis. The tumor necrosis factor (TNF) receptor family member, CD27, is a transmembrane co-stimulatory molecule that is also secreted in a soluble form (sCD27). Recent evidence has suggested that interactions between CD27 and its TNF-like ligand, CD70, play a critical role in regulating B-cell activation and survival, and therefore, may provide a viable therapeutic target for the treatment of WM. Methods: Patients with the consensus panel diagnosis of WM who provided written consent were evaluated. ELISA assay kits were obtained from Bender MedSystems. Flow cytometric analysis, RT-PCR, and calcein ADCC assays were performed as previously described (Santos et al, in press). Results: By ELISA, WM patients displayed dramatically higher levels of sCD27 in their sera (median 7.45, range 0–19.42 U/ml) versus healthy donors (median 0, range 0–2.78 U/ml; p = 2.5 × 10−7). CD27 was expressed in 7/7 patients using RT-PCR analysis, and on the tumor cell surface of 5/12 patients. CD70, the target for CD27, was widely expressed on tumor cells (6/6) and mast cells (10/11) using flow cytometric analysis. To define the functional role of sCD27 in WM, we cultured BCWM.1 (CD27−CD70+) WM cells, LAD1 (CD27−CD70+) mast cells, and primary tumor and mast cells (CD70+) isolated from WM patients with sCD27 (0.1–50 ug/mL), and observed no effect on their proliferation or induction of apoptosis. However, culture of LAD1 and primary WM mast cells (10/10) with sCD27 resulted in marked upregulation of two TNF family ligands which support the growth and survival of WM cells: CD40L (CD154) and a proliferation induction ligand (APRIL). Importantly, the anti-CD70 mAb SGN-70 (1 ug/ml) inhibited this upregulation by sCD27, establishing the specificity of the CD27-CD70 interaction. In addition, SGN-70 demonstrated significant ADCC against BCWM.1 WM cells at dose levels up to 20 ug/ml. Conclusions: Taken together, these studies suggest a novel functional role for sCD27 in the pathogenesis of WM, and demonstrate the feasibility of targeting CD70 and sCD27-CD70 interactions with the SGN-70 monoclonal antibody.

[Table: see text]
A pilot study of a PANVAC-V and PANVAC-F in patients (pts) with metastatic carcinoma
Authors: Gulley J. , Arlen P. M. , Dahut W. L. , Tsang K. , Jones J. , Pazdur M. , Jones E. , Kotz H. L. , Schlom J.
Published: March 2020

2512

Background: The vast majority of carcinomas express either MUC-1 or CEA. Preclinical and clinical studies have demonstrated that induction of T-cell responses directed against CEA and MUC-1 can lead to anti-tumor activity without toxicity. Two novel vaccines have been developed: (a) PANVAC-V (V) a recombinant vaccinia virus containing CEA and MUC-1 with modified agonist epitopes and 3 costimulatory molecule transgenes, and (b) PANVAC-F (F) a similar recombinant fowlpox virus. Methods: This pilot study enrolled 25 pts with metastatic carcinoma who had progressive disease after chemotherapy. Pts received V priming followed by F boosts every 2 weeks × 3 then monthly with restaging scans every 2 months while on study. All vaccines were given with sargramostim at the vaccine site. The primary endpoint was safety. Class I and class II immune responses to CEA were analyzed. Class I responses were assayed by ELISPOT, intracellular cytokine, and tetramer binding; and class II responses were assayed by ELISA using CEA protein and class II peptides. Results: Treatment was well tolerated with 135 cycles given. Only one grade 3 toxicity (syncope during a flu-like illness) was possibly related to vaccine. Apart from injection site reactions, only 9 cycles (7%) were associated with transient grade 2 toxicity (generally flu-like syndromes). Class I and class II immunologic responses were demonstrated. A pt with metastatic breast cancer and 5 large liver metastasis had a 24% decrease in unidimensional measurement of disease for 6 months. A pt with metastatic gastric cancer had stable disease for 5 months. Furthermore, a pt with metastatic clear cell ovarian cancer s/p chemotherapy had complete disappearance of large volume, symptomatic ascites accompanied by marked improvement in the appearance of mesenteric stranding and a CA-125 reduction from 281 U/mL to continued sustained normal values (< 20 U/mL). Conclusions: This vaccine can be given safely and can generate therapy specific immunologic responses. In addition 1 pt with metastatic ovarian cancer had a dramatic clinical response. Based on this, we have initiated a pilot study specifically for ovarian cancer pts to gain more information on which to base a large clinical endpoint trial.

No significant financial relationships to disclose.
Immune evasion by CD200: New approaches to targeted therapies for chronic lymphocytic leukemia (CLL)
Authors: Kretz-Rommel A. , Dakappagari N. , Qin F. , McWhirter J. , Oltean D. , Ravey E. , Wu D. , Springhorn J. , Saven A. , Bowdish K.
Published: March 2020

2519

Background: Although the human immune system is capable of raising an immune response against many cancer types, that response is insufficient to eradicate the cancer in most patients, possibly due to immune evasion through negative regulation of the immune system by the tumor. We identified the immune-suppressive molecule CD200 to be upregulated 1.5–5.4-fold on CLL cells in all 80 patients examined. Interaction of CD200 with its receptor alters cytokine profiles from Th1 to Th2 in mixed lymphocyte reactions, and results in the induction of regulatory T cells, which are thought to hamper tumor-specific effector T cell immunity. We addressed whether CD200 expression on tumor cells plays a role in immune evasion, thereby preventing elimination of tumor cells by the immune system in a xenograft hu/SCID mouse model, and whether treatment with an antagonistic anti-CD200 antibody affects tumor growth. Methods: The human non-Hodgkins lymphoma cell lines RAJI and Namalwa were transduced with human CD200 and injected subcutaneously together with human peripheral blood lymphocytes (PBL) into NOD/SCID mice. Tumor growth over time was compared among mice that either received CD200-expressing tumor cells or received tumor cells lacking CD200 expression. In subsequent experiments, mice were treated with chimeric or humanized anti-CD200 antibodies (doses ranged from 1 to 20 mg/kg) by intravenous injection. Treatment was either started immediately or 7 days after tumor cell injection. Results: As expected, PBLs reduced CD200-negative RAJI or Namalwa tumor growth by up to 75%. In contrast, growth of RAJI or Namalwa tumors expressing CD200 at levels comparable to that of CLL was not reduced by PBLs. Administration of anti-CD200 antibodies at 5 mg/kg resulted in nearly complete tumor growth inhibition (1/10 mice developed a small tumor) over the course of the study even when treatment was started 7 days after tumor cell injection. Conclusions: CD200 expression on tumor cells inhibits the ability of human lymphocytes to eradicate tumor cells. Treatment of CD200-expressing tumors with antagonistic anti-CD200 antibodies inhibits tumor growth, indicating the potential for anti-CD200 therapy as a promising approach for CLL.

No significant financial relationships to disclose.
Effect of interleukin-2 (IL-2) and 13-cis retinoic acid (RA) on vascular endothelial growth factor (VEGF) and durable response in patients with advanced solid tumors showing a partial response (PR) or stable disease (SD) to chemotherapy
Authors: Recchia F. , Saggio G. , Di Blasio A. , Amiconi G. , Cesta A. , Candeloro G. , Alesse E. , Rea S.
Published: March 2020

2521

Background: A large proportion of patients with advanced solid tumors (AST), showing response to chemotherapy, experiences relapse from resistant stem cells that form minimal residual disease (MRD). High serum levels of VEGF have been shown to be associated with MRD and with a short relapse-free survival (RFS). We have shown, that low-dose IL-2 and RA, decreased VEGF and enhanced the immune function of patients with AST responding to chemotherapy (Clin Cancer Res 2001, Anticancer Res 2005). Primary endpoint of this study was to evaluate if IL-2/RA decreased VEGF and restored the immune function in patients with AST that had a PR or SD to chemotherapy. Secondary endpoint was the evaluation of the efficacy of IL2/RA in RFS and overall survival (OS). Methods: 100 consecutive AST patients (66% PR, 34% SD), with a mean VEGF of 520 pg/mm3, were entered into the study from 01/97 to 05/04. Median age was 66 years with 57% males. Diagnosis: Lung 28, head & neck 15, kidney 13, gastric 11, ovary 10, breast 10, miscellanea 13. Therapy consisted of self-administered subcutaneous IL-2, 1.8 X 106 IU and oral RA, 0.5 mg/Kg for 5 days/week for 2 cycles of 3 weeks, with a 1-week rest, for 1 year. Therapy was continued, with intermittent schedules until progression. Immune function and tumor markers were assessed every 2 months, response every 4 months. Results: After a median follow-up time of 42 months (16–106) and 900 courses of therapy, a statistically significant decrease of VEGF (148 pg/mm3, p<0.002) and improvement of lymphocytes, NK and CD4+/CD8+ ratio, with respect to baseline values, was observed. 5-year RFS and OS were 30% and 38%, respectively. 28% of patients were converted to a complete response: Their 5-year RFS and OS were 73% and 94%, respectively. No WHO grade 3 or 4 toxicity was observed, while grade 2 cutaneous toxicity and fever occurred in 20% and 13% of patients, respectively. Conclusions: The administration of IL-2/RA determines, with a low toxicity profile, a statistically significant decrease of VEGF, an improvement of all immunological parameters known to be prognostically relevant and a durable clinical response in 28% of patients.

No significant financial relationships to disclose.
A phase I/II, open label trial of Lewis Y specific monoclonal antibody IGN311 to evaluate safety and efficacy in patients with malignant effusion
Authors: Bauernhofer T. , Samonigg H. , Regitnik P. , Lileg B. , Weizer W. , Waxenecker G. , Kainer M. , Wiederkum S. , Loibner H. , Kircheis R.
Published: March 2020

2547

Background: Treatment of CRC patients (pts) with the humanized mAb IGN311 targeting the carbohydrate Lewis Y eliminated circulating tumor cells in blood and thereby confirmed the clinical profile of the parent murine antibody ABL364, which showed elimination of Lewis Y and cytokeratin positive cells in bone marrow of pts with breast cancer. Methods: An open-label, single treatment arm, uncontrolled study with IGN311 (100mg per dose, intravenously on day 1 and 7) in pts with malignant effusion (ascites or pleural effusion) is being conducted with the primary objective to examine safety and tolerability. Secondary objectives are volumetric measurement of the malignant effusion and to obtain data for several immunological parameters. Results: 4 pts (2 pts with gastric cancer and malignant ascites, 2 pts with breast cancer and malignant pleural effusion / ascites) have completed the study until December 2005. IGN311 was well tolerated with only one patient showing up to grade 2 nausea, vomiting and skin rashes as side effect after 1st application which was easily managed. In all pts significant levels of IGN311 were measured followed by an increase in CD45 positive cells in the effusion. The patient with the highest level of Lewis Y expressing tumor cells showed a reduction of effusion volume during treatment. Conclusions: IGN311 was well tolerated, permeated into malignant effusion and attracted immune cells leading to decreased tumor cell counts in the effusion. In the case of strong Lewis Y expression of malignant cells in the effusion a reduction of the effusion volume could be demonstrated.

[Table: see text]
Vaccination of hormone-refractory prostate cancer patients with peptide cocktail-loaded dendritic cells: Results of a phase I clinical trial
Authors: Meye A. , Fuessel S. , Schmitz M. , Zastrow S. , Linne C. , Richter K. , Lobel B. , Hakenberg O. W. , Hoelig K. , Rieber P. E. , Wirth M. P.
Published: March 2020

2551

Background: For patients with hormone-refractory prostate cancer (HRPC) treatment options are limited. Immunotherapies based on dendritic cells (DCs) might represent promising alternatives. In a Phase I clinical trial, we evaluated the safety and feasibility of a vaccination with monocyte-derived DCs loaded with a cocktail consisting of HLA-A*0201-restricted peptides derived from prostate cancer-associated antigens (PSA, PSMA, survivin, prostein, trp-p8). Methods: Eight HRPC patients were enrolled in this study (Table). Each patient underwent two leukaphereses, for the isolation of monocytes and subsequent generation of mature DCs. Patients received a total of four vaccinations each with peptide cocktail-loaded DCs at a dose of 1 x 107 cells both intradermally and intravenously every other week. Clinical response was monitored by the determination of the PSA level. The induction of a peptide-specific T-cell response was assessed by ELISPOT analysis. Results: Apart from local erythema and edema at the site of intradermal administration no side effects were noted. Four of eight patients showed a temporary PSA decline. One patient displayed a partial response with a PSA decrease > 50% for seven weeks and further stabilization for five weeks. Stable PSA values or decelerated PSA increases were observed in the three remaining patients. In ELISPOT analyses, three of four PSA responders also showed antigen-specific CD8+ T-cell activation against prostein, survivin and PSMA. Conclusions: The described protocol represents a safe and feasible concept for the induction of clinical and immunological responses. The application of a peptide cocktail derived from different antigens as a novel treatment modality is supposed to allow for the genetic and biologic heterogeneity of PCa.

[Table: see text]

[Table: see text]
Immunopharmacology of cancer vaccines: Restoration of NKG2D levels and functions in metastatic melanoma treated with exosomes
Authors: Chaput N. , Andre F. , Menard C. , Escudier B. , Robert C. , Lhomme C. , Zitvogel L. , Tursz T.
Published: March 2020

2554

Background: The C-type lectin-like stimulatory immune receptor Natural Killer group 2 receptor (NKG2D) is expressed by NK and CD8+ T cells. NKG2D engagement is a natural mediator of immunosurveillance which can be compromised by locally sustained ligand expression. In cancer patients with NKG2D ligand- expressing tumors, NK and CD8+ T cells often express low levels of NKG2D and are functionally compromised. Dentritic cell-derived-exosomes (Dex) are nanomeric vesicles harboring functional MHC/peptide complexes capable of promoting T cell immune responses and tumor rejection in mice. Two Dex Phase I trials highlighted the and the safety of exosome administration. The observation of clinical regressions in the absence of detectable T cell responses prompted the search for alternate effector mechanisms. We study NKG2D expression and NK cells function in peripheral lymphocytes before and after Dex therapy. Methods: Exosomes were purified from day 7 autologous monocyte derived-DC cultures. Fifteen patients were enrolled and received exosome vaccinations. NK cells functions prior or following exosome vaccines were tested in standard Na251CrO4 chromium release assays. NKG2D and NKG2D ligand expression were studied using flow cytometry and/or western blot experiments. Results: In sharp contrast with DC, Dex bear functional NKG2D ligands leading to a selective downregulation of NKG2D activating receptors on autologous NK cells in vitro. Long term administration of Dex could enhance NKG2D expression levels on NK and CD8+ T cells in 50% of patients, restoring killing of NKG2D ligand expressing K562 and autologous tumour. In contrast to NKG2D ligands shed by tumors mediating immunosuppressive activity, exosomal NKG2D ligands promote NKG2D-dependent effector functions in vivo, that might account for the non MHC restricted-antitumor effects observed in the trial. Conclusions: NK cell activation represent a new pharmacodynamic for Dex leading to tumor recognition and regression in vivo. The Phase II trial using Dex shall include the monitoring of NKG2D ligands on Dex preparation and follow up NKG2D levels, functions and polymorphism in patients.

No significant financial relationships to disclose.
Intrapericardial cellular immunotherapy for malignant pericardial effusion using autologous IL-2-activated TILs
Authors: Toh U. , Fujii T. , Seki N. , Ogo E. , Shirouzu K. , Yamana H.
Published: March 2020

2555

Background: Pericardial effusion (PE) and cardiac tamponade caused by malignant pericarditis are critical conditions in cancer patients, which still lack a recommended protocol for their long-term management. The aims of this study were to investigate the presence of cytotoxic T lymphocytes (CTLs) in malignant PE and to determine the clinical response to administering autologous tumor-infiltrating lymphocytes (TILs) into the pericardial cavity. Methods: Initially, we identified human lymphocyte antigen class-I-restricted and tumor-specific CTLs within the interleukin-2 (IL-2)-activated TILs in PEs from four patients, on the basis of interferon-g production and lactate dehydrogenase-release assays. Clinically we observed favorable responses to the pericardial transfer of IL-2-activated autologous TILs in four patients: one male with advanced esophageal cancer, one female with recurrent lung cancer and two female with recurrent breast cancer, respectively. Autologous TILs from PEs were expanded in vitro with IL-2, characterized for CD3, CD4 and CD8 markers, checked for contamination and then infused into the patient’s pericardial space through a catheter. This was repeated biweekly. Results: After treatment, there were no signs of recurrence of PE in either case, as determined by radiography, echocardiography and computed tomography. The only adverse effects seen were grade 1 fevers. Conclusions: These results suggested that intrapericardial cellular immunotherapy with autologous TILs could be a safe and effective treatment for controlling malignant pericarditis with associated cardiac tamponade, and that tumor-specific CTLs present in malignant PE might be important for tumor rejection.

No significant financial relationships to disclose.
Hematologic malignancies developing in previously healthy individuals who received hematopoietic growth factors: Implications for use of colony stimulating factors in healthy volunteers participating in early phase clinical studies and in healthy blood product donors
Authors: Lyons A. E. , Balasubramanian L. , Andritsos L. A. , Evens A. , Kuzel T. , Vose J. M. , Bierman P. J. , Kuter D. J. , Devine S. M. , Bennett C. L.
Published: March 2020

2559

Background: Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHu-MGDF aka MGDF) and recombinant granulocyte colony stimulating factor (G-CSF) promote the maturation of hematopoietic progenitor cells. Healthy volunteers/donors have received MGDF in phase I/II clinical trials and G-CSF in allogeneic peripheral blood stem cell transplantation procedures. Herein, we review clinical findings for five previously healthy volunteers/donors who developed hematologic malignancies after the use of MGDF or G-CSF. Methods: Clinical information related to hematologic malignancies were reviewed for three volunteers who had participated in a phase I/II clinical trial with MGDF and two donors who underwent G-CSF mobilized peripheral blood stem cell harvesting procedures for sibling allogeneic stem cell transplantation for acute leukemia. Results: Mantle cell, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia were diagnosed three to five years after exposure among three volunteers who received MGDF. For one of these patients, autoimmune thrombocytopenia and antibodies to MGDF that cross-reacted with endogenous thrombopoietin had developed shortly after MGDF administration and persisted until lymphoma chemotherapy was administered. Following chemotherapy, all three achieved complete remission, although one patient subsequently relapsed. Acute myelogenous leukemia was diagnosed four to five years after exposure in two donors who underwent G-CSF primed stem cell harvests prior to their siblings’ allogeneic stem cell transplantation. Following intensive chemotherapy, one of these patients died from acute leukemia and the second is now in complete remission. Conclusion: Controversy exists over the appropriateness of administering hematopoietic growth factors to healthy individuals. While a causal relationship with hematologic malignancies is uncertain, long-term follow-up among healthy individuals who receive hematopoietic growth factors is needed.

No significant financial relationships to disclose.
Phase I clinical trial of hybrid cell vaccination in patients with gastrointestinal cancer
Authors: Iinuma H. , Okinaga K. , Iwasaki K. , Koide T. , Inaba T. , Fukushima R.
Published: March 2020

2579

Background: Vaccination with hybrid cells of dendritic cells (DCs) and tumor cells can induce specific ant-tumor immunity against multiple tumor antigens including those that are unknown. We report the results of phase I study of hybrid cell vaccines comprised of autologous DC and autologous tumor cells in patients with Stage IV or recurrent gastrointestinal cancer. Method: Thirteen patients with Stage IV or recurrent gastrointestinal cancer were enrolled in this study after informed consent was obtained. Tumor cells were cryopreserved following acquisition from the primary or a metastatic site. DCs were induced from mononuclear cells of patients by culture with cytokines (6 days culture with GM-CSF and IL-4, and a further 1 day culture with TNF-α, IL-1 β, IL-6 and PGE2). Fusion of irradiated tumor cells and DC was created with a combination of PEG and electrofusion (two-step fusion method). At 2 week interval, patients received 4 freshly prepared fusion vaccines, with a constant dose range of 1 × 107 to 4 × 107 cells. The endpoints of this study were assessments of safety, anti-tumor immune response and clinical response. Results: Serious adverse events were not observed in any of the enrolled patients and all Common Toxicity Criteria were grade I. Clinical responses are 1 with partial response (PR), 5 with stable disease (SD) and 7 with progressive disease (PD). Delayed skin tests changed to positive in 5 patients. In patients with PR and SD, a shift to Th1 in Th1/Th2 balance of lymphocytes (IFN γ/IL10, IFN γ/IL4) was demonstrated by ELISPOT and cytokine flow cytometry analysis. After vaccination, decrease of immunosuppressive factors (IAP, TGF-β) in serum were shown in patients with PR and SD. There was no significant differences of CD4+CD25+ cells by vaccination. Conclusion: These results suggests that a strategy of hybrid cell vaccine employing auto-DCs and auto-tumor cells is feasible in patients with gastrointestinal cancer and may show evidence of anti-tumor immune response.

No significant financial relationships to disclose.