bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I study of olaparib in combination with carboplatin and/or paclitaxel in patients with advanced solid tumors.
Authors: van der Noll Ruud , Ang Joo Ern , Jager Agnes , Marchetti Serena , Mergui-Roelvink Marja , De Bono Johann Sebastian , Lolkema Martijn , Brunetto Andre , Arkenau Hendrik-Tobias , De Jonge Maja J. , van der Biessen Diane , Tchakov Ilian , Bowen Karin , Schellens Jan H. M.
Published: March 2020

2579

Background: This three-center phase I study evaluated the PARP1/2 inhibitor olaparib (O) in combination with carboplatin (C), paclitaxel (Pa) or both (CPa) in patients (pts) with advanced solid tumors refractory to standard therapies (NCT00516724). Methods: This ongoing study consists of multiple parts (P) in which escalating doses of O capsule and tablet formulations were studied. Capsule formulation data are presented; continuous O with C (P1; 21 day cycle), CPa (P2a; 21 day cycle) and weekly Pa (P2b; 28 day cycle) or intermittent O with CPa (P3; 21 day cycle). Primary and secondary objectives were safety/tolerability and antitumor activity (RECIST), respectively. Results: This analysis (non validated data) included 87 enrolled pts (P1 [n=25] P2a [n=20] P2b [n=12] and P3 [n=30]). Most common tumor types were breast (26%), melanoma (10%) and ovarian (7%). 12 pts had known gBRCA1/2 mutations. A tolerable continuous dosing schedule of O with CPa was not determined. Most common AEs (all grades) were myelosuppression (71%) notably neutropenia (54%) and thrombocytopenia (26%), and fatigue (77%). Excessive treatment cycle delays due to hematologic toxicity occurred with continuous O combined with standard doses of C or CPa. Two doses were identified as tolerable: continuous O 100 mg bd with weekly Pa 80 mg/m2 and intermittent O 200 mg bd (d1–10) with CPa AUC4/175 mg/m2 q 3 weeks. 14/87 pts (16%) had an objective response (complete response [CR] 5%; partial response [PR] 11%); 28% had stable disease for ≥4 months. Activity appeared greater in pts with BRCA1/2 mutations (CR 17%; PR 33%). Conclusions: Continuous O in combination with CPa exacerbated hematologic toxicities leading to schedule delays. Tolerability improved with intermittent O. Antitumor activity was highest in pts with a BRCA1/2 mutation. This study identified two tolerable O capsule treatment schedules for further development. Clinical trial information: NCT00516724. [Table: see text]
Assessment of γH2AX levels in circulating tumor cells in patients treated with veliparib in combination with doxorubicin and cyclophosphamide in metastatic breast cancer.
Authors: Tan Antoinette R. , Toppmeyer Deborah , Wong Serena Tsan-Lai , Lin Hongxia , Gounder Murugesan , Moss Rebecca Anne , Stein Mark N. , Mehnert Janice M. , Kim Sinae , Chen Alice P. , DiPaola Robert S.
Published: March 2020

2582

Background: Veliparib (V) is a potent PARP inhibitor that delays repair of DNA damage induced by chemotherapeutic agents. In metastatic breast cancer pts, we evaluated V with doxorubicin (A) and cyclophosphamide (C) given both on day 1 with V at 100 mg po BID for 7 days post-chemotherapy every 21 days, to increase DNA damage. We report use of γH2AX, (phosphorylated histone protein), a marker of DNA double-strand breaks, in circulating tumor cells (CTCs) to assess DNA damage. We evaluated number of CTCs and percentage of γH2AX-positive CTCs pre- and post-treatment. Methods: Eligibility included prior A ≤ 300 mg/m2 and EF ≥ 50%. Further A was omitted after a cumulative dose of 420 mg/m2. Primary objective was to assess DNA damage response to treatment by measuring γH2AX-positive CTCs during cycle 1 on days 1 (pre-treatment), 2, 7, and 14. Cell Search System was used to enumerate CTCs. γH2AX was quantitated using a validated assay. Results: Eleven pts enrolled. Median age was 53 (34 – 73); median ECOG PS 1 (0 – 2); there were 1 ER-negative/HER2+, 4 triple-negative (BRCA2+, n =1), and 6 ER+/PR+/HER2-negative (BRCA2+, n =2) tumors. Most common drug-related toxicities were grade (gr) 4 neutropenia, gr 2 anemia and thrombocytopenia, and gr 1 nausea and vomiting. In BRCA2+ pts, there were 2 PRs and 1 SD. In BRCA wt or unknown status, 5 pts had SD ≥ 3 mo and there were 3 PDs. CTCs (≥ 8) were detected in 10/11 pts on days 1 and 2. Day 7 samples were not obtainable in 2 pts. On day 7, 1/8 pts had 0 CTCs and rest had ≥ 3 CTCs. A decrease in CTCs (p < 0.0001) occurred from day 1 (median: 22, range, 8-1216) to day 7 (median: 5, range 3-37). At baseline, 7 pts had ≥ 10% γH2AX-positive CTCs. Fraction of CTCs positive for γH2AX increased to ≥ 50% by day 7 in 6/7 pts and persisted to day 14 in 5 pts. Conclusions: The toxicity profile of V 100 mg BID days 1-7 with AC (60/600 mg/m2) on day 1 on a 21-day cycle was expected. Objective antitumor activity was seen in BRCA mutation carriers. CTCs decreased and percentage of γH2AX-positive CTCs increased after combination treatment with a PARP inhibitor and chemotherapy. This observation is notable and we plan to extend dosing of V to 14 days. This work is supported by NCI U01-CA132194. Clinical trial information: NCT00740805.
Phase I study of ABT-888 in combination with carboplatin and gemcitabine in subjects with advanced solid tumors.
Authors: Bell-McGuinn Katherine M. , Gray Heidi J. , Fleming Gini F. , Cristea Mihaela C. , Medina Diane M. , Xiong Hao , Dudley Matthew W. , Dunbar Martin , Giranda Vincent L. , Luo Yan , McKee Mark D. , Martin Lainie P.
Published: March 2020

2584^

Background: Veliparib (V) is an oral inhibitor of poly(ADP-ribose) polymerases (PARP)-1 and -2, which are essential for base excision repair of ssDNA breaks. BRCA deficient tumors are more sensitive to PARP inhibitors when used as monotherapy or in combination with DNA-damaging agents. The objectives of this study were to determine the maximum tolerated dose (MTD), pharmacokinetic interactions, and safety/tolerability profile of V in combination with carboplatin (C) and gemcitabine (G). Methods: Eligibility criteria included patients (pts) with metastatic or unresectable solid tumors for which C/G was a treatment option. During the study, eligibility was amended to limit prior chemotherapy regimens to ≤ 2. C AUC 4 /G 800 mg/m2was given intravenously on Day 1 and G given on Day 8 of 21 day cycles. To assess tolerability of C/G prior to V, V was started in Cycle 2. When C/G was stopped, pts could stay on monotherapy V until progression. Dose-escalation used a Bayesian continual reassessment method. Results: 59 pts (51 female, median age 52) were enrolled. The most common tumor types were ovarian (n=39) and breast (n=10). Germline BRCA mutations were known in 24 ovarian pts. 58 pts had prior chemotherapy (1-6 regimens, median 2), and 51 had prior platinum. Grade 3/4 AEs in >10% of pts were neutropenia, thrombocytopenia, anemia, and leukopenia. Dose limiting toxicities were thrombocytopenia (n=3) and neutropenia at V 310 mg twice daily (BID) and thrombocytopenia at 250 mg BID. Other frequent AEs were nausea, constipation, and fatigue. Preliminary results showed co-administration of V did not affect C or G pharmacokinetics. Treatment cycles (range, median) were 1-28, 5 for V; 2-10, 5 for C; and 2-10, 4 for G. Day 8 G was stopped in some pts to improve tolerability. 28 pts stayed on monotherapy V (1-23 cycles). Partial and complete responses were seen in 11 and 2 pts. Response rates were 47% (8/17) in known BCRA deficient ovarian, 25% (3/12) in other ovarian, and 13% (2/15) in other evaluable pts. Conclusions: V combined with C and G was tolerated with a safety profile similar to C and G alone. The MTD was V 250 mg BID, C AUC 4.0, G 800 mg/m2. Promising anti-tumor activity was observed in BRCA deficient ovarian pts. Clinical trial information: NCT01063816.
CYP3A4 phenotyping with midazolam to predict sunitinib exposure.
Authors: van Erp Nielka P , de Wit Djoeke , Sparreboom Alex , den Hartigh Jan , den Hollander Margret , Konig-Quartel Jacqueline M.C. , Hessing Trees , Guchelaar Henk-jan , Gelderblom Hans
Published: March 2020

2592

Background: Patients treated with sunitinib show high inter-patient variability in drug exposure (40-60%), which is largely unexplained. Since sunitinib is metabolized by CYP3A4, variability in the activity of this enzyme may explain a considerable proportion of the observed variability. We therefore prospectively studied the relationship between CYP3A4 activity and systemic exposure to sunitinib. Methods: In fifteen patients treated with sunitinib in a four weeks “on” – two weeks “off” regimen the pharmacokinetics of sunitinib and its active metabolite SU12662 were assessed. To determine sunitinib+SU12662 steady-state exposure, samples were collected over 24hrs after at least 14 days of sunitinib therapy. To assess CYP3A4 activity, midazolam 7.5mg orally was administered on the final day of the two weeks “off”. Plasma concentrations were measured over a period of 7hrs to determine midazolam exposure. Exposures (AUC) were calculated using a trapezoidal approach (Phoenix WinNonlin v6.3). The relationship between CYP3A4 activity (midazolam exposure) and sunitinib+SU12662 exposure was determined by linear regression analysis. The percentage of variability in sunitinib+SU12662 exposure that could be explained by CYP3A4 activity was calculated by Pearson’s correlation. In addition, the correlation between sunitinib+SU12662 Ctrough levels and sunitinib+SU12662 exposure was assessed. Results: A strong correlation between midazolam exposure (AUC0-7hr) and steady-state sunitinib+SU12662 exposure (AUC0-24hr) was found (p= 0.002); CYP3A4 activity explained 55% of the observed inter-patient PK variability of sunitinib+SU12662. Furthermore sunitinib+SU12662 Ctrough levels were highly predictive (96%) for overall sunitinib+SU12662 exposure (AUC0-24hr). Conclusions: Midazolam as a phenotyping probe could be useful before start of sunitinib therapy to identify patients at risk for under- respectively overtreatment at a standard dosage regimen. Therefore, CYP3A4 phenotyping could be useful to individualize sunitinib therapy. Additionally, sunitinib+SU12662 trough levels are highly predictive for sunitinib+SU12662 exposure and thus can be used for monitoring and guiding sunitinib therapy in clinical practice. Clinical trial information: NCT01743300.
Investigation of the pharmacogenetic influences of carbonyl reductase on doxorubicin and doxorubicinol in breast cancer patients.
Authors: Gaudy Allison , Fetterly Gerald J. , Adjei Alex A. , O'Connor Tracey L. , Quinones Adolfo , Blanco Javier G. , Ferguson Daniel , Meholick Patricia D. , Kalabus James
Published: March 2020

2594

Background: The anthracycline doxorubicin (DOX) is widely used to treat breast cancer. Doxorubicin is associated with pharmacokinetic and pharmacodynamic variability and despite its use for several years there is limited understanding behind it. Hepatic carbonyl reductases (CBR1 and CBR3) catalyze the reduction of DOX into its main circulating C-13 metabolite doxorubicinol (DOXOL). Polymorphisms in CBR1 and CBR3 influence synthesis of DOXOL, and could potentially play a role in the pharmacokinetic (PK) variability seen with doxorubicin treatment. In this study, we examined the influence of genetic polymorphisms in CBR1 and CBR3 on DOX and DOXOL PK. Methods: DOX was administered IV to 79 breast cancer patients at 60 mg/m2. Population PK modeling was performed on the parent concentration-time profiles with the following patient factors: [BSA (1.4-2.6 m2), weight (40-140 kg), age (25-75), race (78% white), CBR1 rs9024 (78% wild-type), CBR3 V244M (47% wild-type), CBR3 C4Y (20.5% wild-type); followed by model validation. Noncompartmental analysis (NCA) was performed for both DOX and DOXOL and the metabolic ratio was calculated as AUCDOXOL0-24:AUCDOX0-24. Results: A two-compartment model was used to describe DOX PK. Mean predicted (%SEM) clearance (CL), plasma volume (Vp), tissue volume and distribution clearance were 28.1 L/hr (7.72), 22.5 L (3.80), 257 L (13.8) and 13.6L (21.8), respectively. Interpatient variability on CL and Vp were 22.1% and 12.6%, respectively. BSA was found to be a significant predictor of the interpatient variability on CL. No other patient factors were found to be significant on parent drug PK. The metabolic ratio, assessing the conversion of DOX to DOXOL, was stratified by different polymorphisms of CBR1 and CBR3. There were no significant differences in metabolic ratio due to CBR1 and CBR3 genotypes. Conclusions: A PK model was developed that was able to characterize DOX pharmacokinetics. CBR1 and CBR3 polymorphisms were tested as covariates but were not found to be significant contributors to the variable pharmacokinetic profiles of DOX and DOXOL.
CYP3A inhibitors and adverse outcomes in patients treated with docetaxel chemotherapy.
Authors: Swiecicki Paul L. , Atherton Pamela J. , Finnes Heidi D. , Puttabasavaiah Suneetha , Goetz Matthew P.
Published: March 2020

2596

Background: Docetaxel (D) is an anti-mitotic drug metabolized by the cytochrome P450 (CYP) 3A4 enzyme. While case reports have demonstrated a potential association of CYP3A inhibitor use with severe toxicity in D treated patients (pts), there are no data whether co-administration of CYP3A inhibitors with D increases the rate of hospitalization and/or death. Methods: A retrospective cohort of pts treated with D at the Mayo Clinic Rochester from 1/1/09-10/1/11 was identified. Information regarding D and concomitant chemotherapy (starting dose and dose reductions), type of CYP3A inhibitor, growth factor use, hospitalizations and deaths was abstracted. Time to event analyses (either hospitalization or death) were conducted using Kaplan-Meier estimates and proportional hazards modeling. Results: 384 pts (median age 63, range 20-93) received D as monotherapy (48%) or as multi-agent chemotherapy (52%) for a median of 4 cycles. 56 pts were co-administered CYP3A inhibitors (45 moderate, 11 strong). 90 pts were hospitalized during D chemotherapy and 15 died. The mean time to hospitalization was significantly shorter in pts treated with a mod/strong CYP3A inhibitor (186 days) vs not treated (408 days) (p=0.02) . While time to death was not significantly different based on inhibitor use (111 vs. 177 days, p=0.49), time to first event (hospitalization or death) varied significantly according to those on inhibitors (187 days) versus not (397 days) (HR: 1.78, p=0.02). Time dependent analyses indicated that use of multiage chemotherapy (combination vs D monotherapy; HR 1.96, p= 0.002) and chemotherapy dose reduction of either D (HR 0.54, p<0.01) or other chemotherapy (HR 0.61, p=0.02) were significantly associated with the risk of an event. In a multivariate analysis, moderate/strong CYP3A inhibitor use was associated with a higher risk of any event (HR 1.79, p<0.02), independent of the use or dose of either multi-agent chemotherapy or D dose. Conclusions: These are the first data to demonstrate that co-administration of CYP3A inhibitors with D increases the risk of hospitalization and/or death. Oncologists should reconcile medications prior to D administration and mod/strong CYP3A inhibitors should be avoided or used with caution.
Recommended phase (Ph) II dose (RP2D) selection for investigational Aurora A kinase (AAK) inhibitor MLN8237 (Alisertib; A) combined with paclitaxel (P): Clinical pharmacokinetics (PK), drug-drug interaction (DDI) assessment, and translational exposure-efficacy modeling.
Authors: Venkatakrishnan Karthik , Zhou Xiaofei , Ecsedy Jeffrey , Mettetal Jerome , Benaim Ely , Liu Hua , Falchook Gerald Steven , Fingert Howard , Shyu Wen Chyi , Kleinfield Robert , Milton Ashley
Published: March 2020

2598

Background: Two maximum tolerated doses (MTDs) were reported for P/A combination in Ph 1 of NCT01091428 (Falchook, ASCO 2012). Here we report clinical PK/DDI results in the context of preclinical exposure-efficacy relationship for P/A to select RP2D. Methods: Pts with advanced ovarian/breast cancer received A (oral BID D1–3, 8–10, 15–17) with 60 or 80 mg/m2 P on D1, 8, 15 in 28-D cycles, with 3+3 dose escalation of A. PK of P was assessed on cycle 1 D1 (P+A); during cycle 2, A doses were withheld on D1–3 allowing for PK of P to be determined in the absence of A on D1. Isobolographic analysis of the response surface relating area under the plasma concentration-time curve (AUC) of A and P to tumor growth inhibition in mice bearing MDA-MB-231 xenografts incorporated mouse-human ratios of plasma free fraction and maximum tolerated exposures, allowing rank ordering of predicted antitumor activity for combined P and A. Results: MTDs were 80 mg/m2 P + 10 mg BID A (80P/10A) and 60 mg/m2 P + 40 mg BID A (60P/40A), as grade 3/4 toxicities (diarrhea, stomatitis, neutropenia, febrile neutropenia) precluded further escalation. Co-administration with A resulted in a small increase in AUC of P (20–25% at 80P/10A; 10–19% at 60P/40A; Table). AUC of P at 60P/40A was below 80P alone. GeoMean D3 concentrations of A at 80P/10A (340 nM) and 60P/40A (1490 nM) were respectively below and within the reported range (590–6580 nM) for tumor AAK inhibition by A (Cervantes, CCR 2012) for 60P/40A. Exposures of A dosed with P were as expected from previous single agent population PK (Venkatakrishnan, ASCO 2012). Exposure-efficacy modeling and isobolographic analysis predicted a rank-order of efficacy at clinical exposures of P/A: 60P/40A > 80P/10A>80P=60P. Conclusions: Safety, PK, and modeling results support 60P/40A as RP2D, currently employed in Ph 2 of NCT01091428, which is enrolling pts with advanced ovarian cancer. Clinical trial information: NCT01091428. [Table: see text]
Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: A phase III randomized trial of the Gynecologic Oncology Group.
Authors: Tewari Krishnansu Sujata , Sill Michael , Long Harry J. , Ramondetta Lois M. , Landrum Lisa Michelle , Oaknin Ana , Reid Thomas J , Leitao Mario M. , Michael Helen E , Monk Bradley J.
Published: March 2020

3

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
Biomarkers and associations with the clinical activity of PD-L1 blockade in a MPDL3280A study.
Authors: Powderly John D. , Koeppen Hartmut , Hodi F. Stephen , Sosman Jeffrey Alan , Gettinger Scott N. , Desai Rupal , Tabernero Josep , Soria Jean-Charles , Hamid Omid , Fine Gregg Daniel , Xiao Yuanyuan , Mokatrin Ahmad , Wu Jenny , Anderson Maria , Irving Bryan A. , Chen Daniel S. , Kowanetz Marcin
Published: March 2020

3001

Background: PD-L1, which is highly expressed on tumors, is a ligand of PD-1, an inhibitory receptor present on activated T cells. PD-L1 expression is regulated by intrinsic (mutations) and adaptive (tumor infiltrating T cells) mechanisms. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Methods: A Ph I study was conducted with MPDL3280A administered IV q3w in pts with locally advanced or metastatic solid tumors. The expansion cohort required available tumor tissue. In addition, the study included a serial biopsy cohort with tumor sampling prior to and during treatment. Tumor samples were analyzed by IHC and a Genentech immunochip measuring ≈90 immune-related genes to characterize the tumor immune microenvironment at baseline (BL) and/or during MPDL3280A treatment. Further, blood-based biomarkers and circulating immune cell subsets were serially measured. Results: Pretreatment tumor samples were available for IHC from 112 pts and for immunochip from 96 pts.In addition, 23 pts had paired BL and on-treatment samples. Blood-based biomarkers were evaluated in 76 pts. Elevated BL PD-L1 expression by IHC was associated with response to MPDL3280A, and coordinated expression of PD-L1 and CD8+ T-cells was observed. Furthermore, a T-cell gene signature (including CD8, IFNg and Granzyme-A) was associated with treatment response. On treatment, responding tumors showed increasing PD-L1 expression and a Th1-dominant immune infiltrate, providing evidence for adaptive PD-L1 upregulation. Nonresponders showed minimal tumor CD8+ T-cell infiltration and an absence of T-cell activation (measured by Granzyme-A and Perforin expression). Additionally, a subpopulation of pts exhibited changes in circulating cytokines (IFNg) and activated T-cell subsets (HLADR+Ki67+). Conclusions: PD-L1 tumor expression and T-cell gene signature correlate with response to MPDL3280A. MPDL3280A therapy led to T-cell reactivation and restored antitumor immunity. These data provide mechanistic insights into immunotherapy and support pt selection for treatment with MPDL3280A monotherapy. Clinical trial information: NCT01375842.
Randomized phase II clinical trial of the anti-HER2 (GP2) vaccine to prevent recurrence in high-risk breast cancer patients: A planned interim analysis.
Authors: Trappey Francois , Berry John S. , Vreeland Timothy J , Hale Diane F. , Sears Alan K. , Ponniah Sathibalan , Perez Sonia A. , Clifton Guy T. , Papamichail Michael , Peoples George Earl , Mittendorf Elizabeth Ann
Published: March 2020

3005

Background: A prospective, randomized, multi-center, placebo-controlled, single-blinded, phase II trial was designed to evaluate the safety and clinical efficacy of GP2, a HER2-derived peptide vaccine, in breast cancer patients. Methods: Clinically disease-free, node-positive or high-risk node-negative patients (pts) with any level of HER2 expression were enrolled after standard of care therapy. HLA-A2+ pts were randomized to receive GP2 + GM-CSF (VG) or GM-CSF alone (CG). HLA A2- controls from a parallel arm of the study were also eligible for evaluation, the extended CG (ECG). Pts receive 6 monthly intradermal inoculations (R0-R6) during the primary vaccine series followed by four boosters every 6 mos. Immune responses (IR) were measured by delayed type hypersensitivity (DTH) at R0 and R6. This planned interim analysis was performed at 24 months median follow-up. Results: We have currently enrolled 172 pts (46, VG; 43, CG; 83 extended CG). There are no differences between groups with respect to age, rate of node positivity, tumor grade, tumor size, ER/PR status, and HER2 over-expression (all p > 0.05). Maximum local toxicity (tox) was similar between the two groups (grade (Gr) 1 and 2: VG 93%, CG 98%; Gr 3: VG 2%, CG 1%). Maximum systemic tox was also similar between the groups (Gr 1 and 2: VG 91%, CG 85%). No Gr 3 systemic tox has been reported. The most frequent systemic reactions are fatigue, headache, and myalgias. IR to GP2 has been robust. DTH is increased from R0 to R6 in the VG (3.0±0.98 to 21.5±4.04 mm, p < 0.01) vs. the smaller increase in CG (2.6±0.89 to 6.0±1.6 mm, p = 0.01). VG DTH at R6 is significantly higher than the CG (21.5 vs 6.0 mm, p < 0.01). The recurrence rate (RR) is decreased in the VG vs CG (4.3% vs. 11.6%, p = 0.41) and VG vs ECG (4.3% vs 9.5%, p = 0.41). In pts with HER2-overexpressing (IHC3+ or FISH+) tumors, the RR is decreased in the VG (0% vs 5% CG, p = 0.28). For TNBC (HER2 low, ER/PR-) pts, the RR is reduced in the VG vs ECG (0% vs 10.6%, p = 0.251). Conclusions: The GP2 vaccine is safe and the minimal toxicity is comparable between the VG and CG, suggesting that it is due to GM-CSF. Robust in vivo immune response has correlated with a >50% reduction in breast cancer recurrences in the VG. Clinical trial information: NCT00524277.
Nonclinical evaluation of the combination of mouse IL-21 and anti- mouse CTLA-4 or PD-1 blocking antibodies in mouse tumor models.
Authors: Jure-Kunkel Maria , Selby Mark , Lewis Katherine , Masters Gregg , Valle Jose , Grosso Joseph , Dito Gennaro , Curtis Wendy , Garcia Richard , Holdren Matthew , Korman Alan J. , Dillon Stacey
Published: March 2020

3019

Background: Interleukin 21 (IL-21), a γc chain family cytokine, is produced primarily by CD4+ T cells and has many effects on immune cells, including enhancing CD8+ T cell and NK cell proliferation and cytotoxicity. Recombinant IL-21 (rIL-21) therapy resulted in objective responses in ~20% of melanoma and renal cell carcinoma patients. In mouse models, monoclonal antibody (mAb) blockade of CTLA-4 prolongs antigen-specific T cell responses, while blockade of programmed death 1 (PD-1) reverses tumor induced T cell suppression. Ipilimumab, a CTLA-4 blocking mAb, significantly improved overall survival in patients with metastatic melanoma in 2 phase III trials, and in phase I studies a PD-1 blocking mAb (nivolumab) has antitumor activity in various cancers. Side effect profiles for each mAb have been related to their mechanism and are generally manageable. It was hypothesized that combination of IL-21 plus CTLA-4 or PD-1 blockade may enhance antitumor responses, potentially leading to improved clinical activity. Methods: Preclinical studies were conducted to test the antitumor activity of mouse IL-21 (mIL-21) in combination with an anti-mouse PD-1 (mPD-1) mAb (4H2-IgG1) or with an anti-mCTLA-4 blocking mAb (9D9-IgG2b) in syngeneic mouse tumor models, including MC38, CT-26, EMT-6, and B16F10. mIL-21 was tested at doses ranging from 50-200 μg/dose, administered up to 3d/wk. mCTLA-4 mAb or mPD-1 mAb were administered 3-4x total at 200-300 μg/dose. Results: Combination treatments produced enhanced antitumor activity vs. monotherapy. In the MC38 model, mIL-21 treatment led to 30% median tumor growth inhibition (TGI) by d29, while mPD-1 mAb produced 60% median TGI and 1/10 tumor-free mice. Combination of both agents led to synergistic antitumor activity, with complete regressions (CR) in 7/10 mice and 99.9% median TGI (p=0.046). CTLA-4 mAb + mIL-21 also produced synergistic activity in the MC38 model. By d21, mIL-21 monotherapy induced 34% TGI while CTLA-4 mAb resulted in 28% TGI, with no CR in either group. Combination resulted in 6/8 mice with CR and 86% TGI (p<0.05). Conclusions: These results support the use of rIL-21+nivolumab and rIL-21+ipilimumab in recently initiated clinical trials.
Anti-CD20-interferon-alpha fusion protein has superior in vivo activity against human B-cell lymphomas compared to rituximab and enhanced complement-dependent cytotoxicity in vitro.
Authors: Yamada Reiko E , Steward Kristopher K , Ngarmchamnanrith Gataree , Trinh Ryan K , Khare Sanjay , Sachdev Raj , Grewal Iqbal S , Morrison Sherie L , Timmerman John
Published: March 2020

3024

Background: We previously reported an anti-CD20-interferon (IFN)-alpha fusion protein able to induce apoptosis and promote in vivo eradication of a human CD20-expressing mouse B cell lymphoma (Xuan et al, Blood 2010). We now report the activity of a recombinant anti-CD20-human IFNα fusion protein against human non-Hodgkin B cell lymphomas (NHL). Methods: Anti-CD20-hIFNα was evaluated against a panel of human Burkitt, diffuse large B cell (DLBCL), and mantle cell lymphoma cell lines. Proliferation was measured by [3H]-thymidine, complement-dependent cytotoxicity (CDC) by PI flow cytometry, and antibody-dependent cellular cytotoxicity (ADCC) by LDH release using PBMC effectors. NHL xenografts were grown in SCID mice. Results: Anti-CD20-hIFNα induced stronger growth inhibition than rituximab, particularly against Burkitt and germinal center-type DLBCL NHLs. Tumor growth inhibition by anti-CD20-hIFNα was associated with substantial apoptosis in some cell lines. Anti-CD20-hIFNα exhibited potent ADCC activity against Daudi, Ramos, and Raji cells, identical to rituximab. Surprisingly, anti-CD20-hIFNα exhibited superior CDC compared to rituximab against Daudi, Ramos, and Raji cells, that was dependent upon linkage of IFNα to the anti-CD20 antibody, and correlated with improved complement fixation. Importantly, anti-CD20-hIFNα achieved superior efficacy compared to rituximab and control fusion protein against multiple NHL xenografts in SCID mice (Raji: p=0.002 and OCI-Ly19: p<0.0001). At antibody doses at which Raji xenografts progressed through rituximab, anti-CD20-hIFNα eradicated 50-88% of established tumors. Non-targeted control fusion protein had only minor effects on tumor growth. Conclusions: Anti-CD20-hIFNα has stronger direct anti-proliferative and CDC activities than rituximab against human NHL while retaining potent ADCC activity, and also has the ability to eradicate established NHL xenografts in vivo. These results support the further development of anti-CD20-hIFNα for the treatment of B cell NHL, and a phase I first-in-human clinical trial is currently being planned.
A phase I study of indoximod in combination with docetaxel in metastatic solid tumors.
Authors: Jackson Erica , Dees Elizabeth Claire , Kauh John S. , Harvey R Donald , Neuger Anthony , Lush Richard , Antonia Scott J. , Minton Susan E. , Ismail-Khan Roohi , Han Hyo S. , Vahanian Nicholas N. , Ramsey William Jay , Link Charles J. , Streicher Howard , Sullivan Daniel , Soliman Hatem Hussein
Published: March 2020

3026

Background: The indoleamine-2, 3-dioxygenase (IDO) pathway catabolizes tryptophan to create a state of immunosuppression. Indoximod (1-methyl-(D)-tryptophan, D-1MT) is an IDO pathway modulator. Preclinical studies in MMTV-neu mouse models have shown indoximod combined with chemotherapy was more effective in causing tumor regression than either agent alone. Based on this data, a phase IB trial was designed to study the safety of the combination of docetaxel (Doc) and indoximod. The primary goal of this trial was to determine the MTD for the combination of Doc and oral indoximod. Secondary endpoints were PK data and efficacy for indoximod/Doc. Methods: This phase IB study consisted of 5 dose levels (DL). Doc was dosed IV q 3 wks at 60 mg/m2 in DL 1-4 and 75 mg/m2 at DL 5. Indoximod was dosed at 300, 600, 1,000, 2,000, and 1,200 mg PO BID continuously in DL 1-5 respectively. MTD was determined using a 3+3 design. The DLT rule was 1st cycle ≥G3 non-heme AEs or ≥G4 heme AEs despite supportive care or that delay therapy >14d. The PK of indoximod and Doc was analyzed using a HPLC assay. PK was measured on C1D1 and 8. Standard eligibility/exclusion criteria applied along with exclusion of patients previously treated with ipilumimab. Treatment was continued until disease progression, intolerance, or unacceptable side effects. Results: Total # of patients treated at DL1-5 were 7, 6, 6, 2, and 6 respectively, with 22 total patients evaluable for response. DLTs included: G3 dehydration (at 300 mg), G5 neutropenic colitis (at 600 mg), G3 hypotension (at 2,000 mg) and G3 mucositis (at 2,000 mg). DL 5 was well tolerated and is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%). There were 4 PRs (2 breast, 1 NSCLC, 1 thymic), 9 SD, and 9 PD. There were no drug-drug interactions, and PK was similar to Doc and indoximod single-agent studies. Conclusions: The Doc+ indoximod combination was well tolerated with no increase in expected toxicities or unexpected PK interactions. It was active in a pretreated population of patients with metastatic solid tumors. The RP2D is 75 mg/m2 of Doc with 1,200 mg of indoximod BID for the current phase II metastatic breast cancer trial. NCT01191216 Clinical trial information: NCT01191216.
A novel method to identify and monitor endogenous tumor-reactive T cells by high expression of CD11a (LFA-1) and PD-1 (CD279) as immunologic readout for evaluating the efficacy of PD-1 blockade.
Authors: Dong Haidong , Markovic Svetomir , Krco Christopher J , Kwon Eugene D.
Published: March 2020

3037

Background: Tumor immunotherapies directed towards enhancing natural or endogenous anti-tumor T-cell immunity in patients with advanced malignancies are currently being implemented in clinic with promising results. In order to optimize therapeutic protocols and monitor the effectiveness of such therapies, a reliable T-cell marker is needed. Methods: We utilized CD11a (LFA-1, lymphocyte functional-associated antigen 1), an integrin up-regulated on effector and memory CD8 T-cells, and PD-1 (programmed death-1), an immunoregulatory receptor expressed by activated T cells, as biomarkers to identify, quantitate and monitor endogenous tumor-reactive cytotoxic lymphocytes (CTLs) in two mouse tumor models and the peripheral blood (PB) of 12 patients with stage IV melanoma. Results: High expression of CD11a and PD-1 was identified among CD8 T-cells residing within primary and metastatic murine tumor sites, as well as in spontaneous murine breast cancer tissues. In the PB of melanoma patients, tumor antigen-specific CD8 T cells were associated with a population of CD11a high CD8 T-cells which co-expressed high levels of PD-1, as opposed to eleven healthy donors who had a much lower frequency of PD-1+ CD11a high CD8 T-cells (p <0.0001). Phenotypic analysis showed that CD11a high CD8 T-cells are proliferating (Ki67 positive) activated (CD62L low, CD69 high) T-cells. Increased CD11a high CD8 T-cells and delayed tumor growth were observed in PD-1 deficient mice, suggesting that the antitumor effector function of CD8 T cells is compromised by co-expression of elevated levels of PD-1. Conclusions: CD11a high CD8 T-cell population expresses high levels of PD-1 and is likely the cellular target of PD-1 blockade therapy. High expression of CD11a (LFA-1) and PD-1 (CD279) by CD8 T-cells may represent a novel biomarker to identify and monitor endogenous tumor-reactive CTLs. This may not only provide an immunological readout for evaluating the efficacy of therapy, but also contribute to the selection of patients with solid malignancies likely to benefit from anti-PD-1 therapy.
Phase I study of weekly treatment with paclitaxel injection concentrate for nanodispersion (PICN), a novel solvent and protein-free formulation of paclitaxel.
Authors: Jain Minish Mahendra , Deshmukh Chetan Dilip , Bondarde Shailesh Arjun , Bhatt Niraj , Shinde Vijay , Bhowmik Shravanti , Divekar Ganesh
Published: March 2020

3039

Background: PICN is a novel solvent and protein-free 100-110 nm particle formulation of paclitaxel stabilized with polymer and lipid using Nanotecton Technology. Paclitaxel has shown superior safety and efficacy profile when administered on a weekly schedule. We studied safety, tolerability, and pharmacokinetics (PK) of PICN using a weekly schedule in patients with advanced solid malignancies. Methods: Patients aged18-65 years with advanced solid malignancies, ECOG performance status ≤ 2, estimated survival ≥ 12 weeks, and adequate organ function were enrolled. A standard phase I, 3+3 dose escalation design to determine the maximum tolerated dose (MTD) of PICN administered on a weekly schedule (three consecutive weeks, one week recovery) was employed. PICN dose was escalated at pre-determined fixed dose levels of 80, 100, 125, 150, 175, and 200 mg/m2. PICN was administered as a 30 min infusion without any premedication for hypersensitivity. Results: Twenty-one patients treated with PICN had a mean age of 52.1 yrs (range 35-67); 20 were female and entered with metastatic breast cancer (MBC; n=15), cervical cancer (n=3), skin cancer (n=2). One male had oral cancer. Doses studied were 80 (n=3), 100 (n=3), 125 (n=3), 150 (n=3), 175 (n=6), and 200 (n=3) mg/m2. Despite the lack of dexamethasone premedication, no patient receiving PICN reported hypersensitivity reaction. Two DLTs (neutropenia and febrile neutropenia; both grade 3) were reported at PICN 200 mg/m2. PICN PK (AUC0-24, AUC0-∞, and Cmax) increased in a dose proportionate manner from 80 to 200 mg/m2. Grade 3 or worse related AEs were: neutropenia, leucopenia, peripheral neuropathy, febrile neutropenia, anemia, thrombocytopenia, fatigue, syncope, hypotension and maculopapular rash. Partial responses were observed in MBC (100, 125, 150, 175, and 200 mg/m2) and cervical cancer (80 mg/m2). Conclusions: PICN on thrice monthly schedule was tolerable in the dose range evaluated. Two DTLs were reported: neutropenia and febrile neutropenia (both grade 3). Anti-tumor activity was observed in MBC and cervical cancer. Final trial data for PICN PK, safety, and efficacy will be presented at the conference. Clinical trial information: CTRI/2011/11/002124.
Circulating endothelial microparticles (EMP) modifications as predictive biomarkers of resistance to chemotherapy for breast cancer (BC).
Authors: Garcia-Garre Elisa , Luengo-Gil Gines , Montoro-Garcia Silvia , Zafra Marta , Gonzalez-Billalabeitia Enrique , de la Morena Pilar , Garcia-Martinez Elena , Lip Gregory Y , Vicente Vicente , Ayala Francisco
Published: March 2020

3042

Background: Growing evidence indicates that EMP may both modulate angiogenesis and endothelial injury in cancer and cardiovascular disease. However, it has not been shown whether in vivo release of EMP might reflect the tumor response or the antiangiogenic effects of chemotherapy (CT). The aim of this work was to evaluate the relationship between the levels of small-size EMP (sEMP) and resistance to CT in locally advanced and metastatic BC. Methods: Citrated platelet-free plasma was obtained from BC patients before and after 3-4 cycles of chemotherapy. Small-size CD144+ sEMP (0.1-0.5 μm diameter) were prospectively quantified using a high resolution Apogee A50 flow cytometer. Association of EMP with clinical variables, response to CT and survival was analyzed. Response (partial or complete) was defined by RECIST criteria. Results: 45 BC patients were included (20, metastatic; 25, locally advanced). Treatment included anthracyclines in 66.7% of patients and taxanes in 15.5%. Small-size EMP baseline counts were higher in premenopausal women (p=0.008), but no association with other clinical or pathological characteristic was found. A significant decrease of circulating sEMP was observed after treatment with CT in the whole group of patients with paired samples available (n=33): pre-CT: 416.2 ± 365 vs. post-CT: 340.7 ± 458 (p=0.005). Lower chemotherapy-induced sEMP decrease was associated to treatment resistance: ROC analysis demonstrated a 66.7% sensitivity and 72.2% specificity of lower sEMP decrease for lack of response to CT using a decline cut-point of -40 sEMP (close to median decrease: -47). With the same cut-point of low sEMP decrease, odds ratio for treatment resistance was 5.2 (95% confidence interval, 1.17-23.04; p=0.03). No clear association of the degree of sEMP decrease was found for disease or progression free survival in the neoadjuvant or in the metastatic setting. Conclusions: This study suggests that circulating sEMP decrease after CT and are tightly associated with treatment resistance in BC patients. These findings indicate pathophysiological roles for sEMP in BC and support their potential role as treatment resistance biomarkers.
Clinical and pharmacodynamic (PD) results of a phase I trial with AMP-224 (B7-DC Fc) that binds to the PD-1 receptor.
Authors: Infante Jeffrey R. , Powderly John D. , Burris Howard A. , Kittaneh Muaiad , Grice Jessica Houston , Smothers James F , Brett Sara , Fleming Margaret E. , May Rena , Marshall Shannon , Devenport Martin , Pillemer Stanley , Pardoll Drew M. , Chen Lieping , Langermann Solomon , LoRusso Patricia
Published: March 2020

3044

Background: PD-1/B7-H1 (PD-L1) axis blockade can reinvigorate T cells, and overcome tumor immune evasion of multiple tumor types. AMP-224 is the first recombinant B7-DC-Fc fusion protein tested in patients that binds to and modulates the PD-1 axis through a unique MOA. The MoA hypothesis for AMP-224 is depletion of PD-1high expressing T-cells representing exhausted effector cells. Subsequent replenishment of the T-cell pool with functional T-cells may restore immune function. Methods: Patients with advanced solid tumors received low dose CTX on Day 0, followed by AMP-224 (IV infusion) on Days 1 and 15 of each 28-day cycle in doses ranging from 0.3 to 30 mg/kg. Blood samples were assessed serially for changes in lymphocyte subsets, PD-1HIT cells and T cell effector function. IHC staining of paired biopsies for B7-H1, CD8, PD-1, CD4 and FoxP3 was performed to assess immunological status of the tumor at baseline and following treatment and then relative to peripheral readouts. Results: 42 patients (83% melanoma) were treated with varying doses of AMP-224 [0.3 mg/kg (n = 6); 1 mg/kg (n=4); 3 mg/kg (n = 4); 10 mg/kg (n = 22); 30 mg/kg (n = 6)]. Infusion reactions were common (69% across dose cohorts) and occurred mostly at higher doses (86% at the 10 mg/kg dose). No drug-related inflammatory adverse events were identified contrary to PD-1 blocking antibodies. Fresh pre-treatment biopsies were collected from 33/42 (78.5%) patients and paired biopsies have been collected thus far from 19/36 (52.7%) patients on study. 31% of baseline tumors were B7-H1+. Several PD readouts in the periphery showed reductions in PD-1HIcells and emergence of a functional T cell response (increases in IFNg+, TNFa+, IL-2+ CD4 and CD8 T cells) in individual patients where partial response, stable disease, and mixed responses were seen. Conclusions: Data from peripheral readouts is consistent with hypothesized AMP-224 MoA. B7-H1+ was not always predictive of functional response to AMP-224 immunotherapy. Comprehensive PD readouts and evaluation of PK/PD relationships will be presented and may ultimately predict restoration of immune competence even in the presence of initial disease progression. Clinical trial information: NCT01352884.
Pharmacokinetics (PK) of blinatumomab and its clinical implications.
Authors: Wu Benjamin , Hijazi Youssef , Wolf Andreas , Brandl Christian , Sun Yu-Nien , Zhu Min
Published: March 2020

3048

Background: Blinatumomab is an investigational, bispecific, single-chain T cell engaging (BiTE) antibody of 55 kD that targets CD19 on B cells and CD3 on T cells. Blinatumomab induces polyclonal T cell activation and proliferation, resulting in redirected lysis of CD19+target cells. Comprehensive analysis of its PK and the clinical implications is presented. Methods: PK data from 131 patients enrolled in 3 phase 1 or 2 studies of non-Hodgkin lymphoma (NHL; N=76), relapsed/refractory acute lymphoblastic leukemia (r/r ALL; N=36), and ALL with minimal residual disease (MRD; N=19) were analyzed. Blinatumomab was given by constant IV (cIV) infusion at 0.5, 1.5, 3, 5, 10, 15, 30, 60 and 90 μg/m2/d over 4 weeks/cycle. Serum blinatumomab concentrations were assessed using a validated bioassay. PK parameters, including volume of distribution (V), half-life (t1/2) and clearance (CL), were analyzed with noncompartmental methods. CL was derived by dividing infusion rate by blinatumomab concentration at steady state (Css). Mean CL from each patient was used to determine disease heterogeneity and for covariate analyses. Effective dose was assessed with PK, in vitroand clinical B cell data. Results: At the doses tested, blinatumomab had linear PK that was stable over time. V (~5 L) approximated that of monoclonal antibodies. Blinatumomab had a t1/2 of ~2 h, with systemic CL of ~2 L/h. Minute blinatumomab concentrations were detected in the urine of 3 (of 13) NHL patients at a dose of 60 μg/m2/d. There was no trend of NHL, r/r ALL or ALL with MRD; CrCL, age, gender, weight, or body surface area (BSA) influencing CL. Preliminary analysis showed comparable mean CL values in patients with CrCL ≥30 mL/min, ranging from 1.9 to 2.6 L/h. To achieve Css above the in vitro EC90 value for leukemia cell lines (470 pg/mL) and complete B cell suppression in patients, 15 μg/m2/d of blinatumomab given as cIV over 4 weeks/cycle is desired for ALL treatment. Conclusions: Blinatumomab PK was linear, stable, and independent of NHL, r/r ALL or ALL with MRD. Kidney involvement in its excretion was limited at the investigated doses. cIV administration is required due to the short t1/2. Flat or BSA-based dosing can be used in adults. A cIV dose of ≥15 μg/m2/d provides adequate exposure for ALL treatment. Clinical trial information: NCT00274742, NCT01209826, NCT00560794.
An engineered immunotherapy (NKTR-214) with altered selectivity toward the IL2 receptor: Efficacy and tolerability in a murine tumor model.
Authors: Charych Deborah H. , Addepalli Murali , Lee Steve , Chang Thomas , Liu Xiaofeng , Pena Rhoneil , Sweeney Terry , Hoch Ute , Doberstein Stephen K. , Kantak Seema S.
Published: March 2020

3060

Background: Cytokine-based immunotherapy has been successful for the treatment of cancer, with potential for durable responses in multiple indications. One approach towards stimulating the immune system is to target the heterotrimeric interleukin2 receptor, IL2R. NKTR-214 uses polymer technology to alter receptor subunit selectivity to favor expansion of CD8+ memory effector T cells (CD8T) in the tumor over CD4+ regulatory T cells (Treg). In addition, polymer conjugation is designed to improve exposure and enhance tumor localization, significantly improving efficacy, modulating vascular leak syndrome (VLS) and allowing flexible dosing regimens. Methods: C57BL/6 mice bearing established subcutaneous B16F10 melanoma were treated with NKTR-214 at a variety of doses (0.25-4.0 mg/kg) and schedules (q5dx3 to q14dx2). Mice treated with clinically validated IL2 were administered 3mg/kg, bidx5 for 2 cycles. Efficacy was measured by monitoring tumor volumes. Tolerability was evaluated by survival. VLS was measured by injection of Evans Blue dye followed by colorimetry in lungs. Tumor immunotyping, by flow cytometry. Results: Tumors from mice receiving NKTR-214 had a CD8/Treg ratio of over 1,000 versus 14 for IL2. NKTR-214 administered at 2 mg/kg, q9dx3 was identified as the optimal regimen and showed tumor growth delay of 26 days compared to 9 days for optimally dosed IL2. 90% of NKTR-214 treated mice tolerated treatment compared to 67% for IL2. VLS was completely resolved prior to administration of the next dose of NKTR-214, unlike IL2. NKTR-214 was well tolerated in rats at two schedules, at MTD. Conclusions: NKTR-214 is a highly differentiated cytokine with a new mechanism of action that may provide options for cancer immunotherapy. Polymer conjugation of a clinically validated cytokine alters the IL2R selectivity to favor expansion of tumor killing immune cells (CD8T) over regulatory immune cells (Treg) in the tumor. The conjugate is also designed to improve exposure and enhance tumor localization, offering more options of dose and schedule. The optimal dose and schedule is cytokine-sparing, provides substantial tumor growth delay, and reduces toxicity.