bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I study of oral LBH589, a novel deacetylase (DAC) inhibitor in advanced solid tumors and non-hodgkin’s lymphoma
Authors: Prince H. M. , George D. , Patnaik A. , Mita M. , Dugan M. , Butterfoss D. , Masson E. , Culver K. W. , Burris H. A. , Beck J.
Published: March 2020

3500

Background: LBH589 is a novel deacetylase inhibitor (DACi) which induces apoptosis of tumor cells at nanomolar levels. In this phase 1 study, we evaluated the safety and tolerability of LBH589 in pts with advanced solid tumors or non-hodgkins lymphoma. Methods: LBH589 was administered orally on Monday, Wednesday, and Friday (MWF) weekly. Western blots on peripheral blood lymphocytes were used to study histone acetylation (HA). Plasma PK profiles were analyzed on Days 1 and 15. Results: Thirty two pts have been treated (Median age 63 years; 18 M, 14 F). Pts received 15 mg (3), 30 mg (10), the dose-limiting toxicity level (DLT), or 20 mg (19), the maximum tolerated dose (MTD). Tumor types included: CTCL (10), renal cell (6), melanoma (6), prostate (4), hepatic (1), rhabodomyosarcoma (1), mesothelioma (1), colon (1), bladder (1), and parotid gland (1). Three DLTs were reported; G3 diarrhea and transient G4 thrombocytopenia at 30 mg and G3 fatigue at 20 mg. The most common adverse events were anorexia, nausea, fatigue, diarrhea and transient thrombocytopenia. Of the 1,057 ECGs, 1 pt (20 mg) had a QTcF of 503 msec, an isolated event after the first dose with no recurrence on continued therapy. The mean change in QTcF from baseline was < 10 msec during the first cycle in all cohorts. No increase in HA was seen at 15 mg, but did increase in 50% of pts at 72 hrs post dose in both the 20 mg and 30 mg cohorts. LBH589 was rapidly absorbed in plasma (Tmax 1.5 hr), then declined with a mean terminal half-life of 16 hrs. Cmax and AUC increased linearly with doses between 15–30 mg. Two cutaneous T- cell lymphoma (CTCL) pts achieved a complete response (5 and 7 months) and 4 CTCL pts attained a partial response (6.5, 8, 9 and 18+ months). Stable disease was achieved in 7 pts: CTCL-2 pts (2 and 3 months); RCC-2 pts (3.5 and 7 months); melanoma-1 pt (4 months), mesothelioma-1 pt (2.5 months) and parotid gland-1 pt (5 months). Fifteen pts progressed on treatment and 4 pts were not evaluable for response. Conclusions: At 20 mg MWF every week, LBH589 oral produced a sustained pharmacodynamic effect on HA for ≥72 hours post dose in 50% of pts. Cardiac data indicates no clinically-significant effect on QTcF. Preliminary evidence of tumor response was observed at this dose and schedule in CTCL pts.

No significant financial relationships to disclose.
A phase 1b study of oral rapamycin (sirolimus) in patients with advanced malignancies
Authors: Ratain M. J. , Napoli K. L. , Moshier K.Knightley , Jiang X. , Fleming G. F. , Gajewski T. F. , Jacobsen E. , Cohen E. E.
Published: March 2020

3510

Background: Rapamycin (R) analogues are being studied as cancer therapies since mTOR is recognized as a relevant target in several cancer types. However, R is readily available, has been well-studied in organ transplant patients, was the first recognized mTOR inhibitor, and demonstrates efficacy in preclinical cancer models. The aims of this study were to define R’s maximum tolerated dose (MTD), observed toxicities, dose-limiting toxicities (DLT), pharmacokinetics and effect on inhibition of phosphorylation of p70 S6 kinase (S6K) in peripheral T-cells (PTL). Methods: R was administered orally once weekly to successive cohorts of patients using an adaptive escalation design based on whole blood concentrations ([R]), using a validated HPLC procedure. S6K was assessed by stimulating CD3+ cells ex-vivo with PMA and ionomycin for 1 hour, followed by Western blot analysis using antibodies directed against phospho-Thr389 of S6K versus total S6K as a loading control. Results: 24 subjects have been enrolled in dose cohorts of 10 mg, 20 mg, 30 mg, and 60 mg. The mean [R] observed on day 2 of week 1 (24 hr after 1st dose) was 5.5±2.7, 11.6±6.0 and 22.6±10.7 ng/mL, for dose levels 10 mg, 20 mg and 30 mg, respectively. [R] decreased by ∼50% by day 4 of week 1 (2.7±1.0, 6.9±4.0 and 11.0±7.7 ng/mL, respectively). By day 1 of week 2 (prior to the next dose of R), [R] had decreased below the limit of quantitation (2 ng/mL) for all subjects at 10 mg, 3 of 7 at 20 mg, and 4 of 6 at 30 mg. Preliminary analysis suggests that sustained phospho-S6K inhibition was achieved in some patients at 30 mg. The most common toxicities observed included nausea (50%), diarrhea (42%), asthenia (38%), hyperglycemia (58%), anemia (46%), and lymphopenia (33%). DLTs observed include 1 patient with grade 3 pneumonia at 20 mg, 1 patient with grade 3 dehydration at 30 mg, and 1 patient with grade 3 asthenia at 60 mg. Stable disease has been observed in 46% of evaluable patients. Conclusions: R can be feasibly administered orally on a once weekly schedule with a similar toxicity and pharmacokinetic profile compared with other mTOR inhibitors. Preliminary evidence suggests that prolonged suppression of phospho-S6K in PTL is possible at well-tolerated doses.

No significant financial relationships to disclose.
A randomized phase II study of two different schedules of RAD001C in patients with recurrent/metastatic breast cancer
Authors: Ellard S. , Gelmon K. A. , Chia S. , Clemons M. , Kennecke H. , Norris B. , McIntosh L. , Seymour L.
Published: March 2020

3513

Background: RAD001C exerts antiproliferative and antiangiogenic effects by mTOR (mammalian target of rapamycin) inhibition. mTOR is critical in the transduction of proliferative signals mediated via the PI3K/Akt pathway. This signal transduction pathway is relevant to HER2 and ER signaling, and in PTEN mutated tumors, thus mTOR may be a central and relevant factor in breast cancer. Methods: Multi-center randomized phase II study assessing two oral schedules of RAD001C: Arm A (A)_10 mg daily, or Arm B (B)_70 mg weekly, assessed clinically each 4 weeks, imaged each 8 weeks. Eligibility: Patients (pts) with measurable metastatic breast cancer (MBC) who may have received adjuvant chemotherapy (CT), with up to one prior CT for advanced/recurrent disease. Stratification factors: 0 or 1 prior CT for MBC; presence/absence of visceral metastases. Primary endpoint: clinical/radiologic response and early progression (<8 wks). Two-stage accrual design with 15 evaluable pts in each arm in first phase. If =1 response and <10 early PD, add 15 pts. Arm B was discontinued after stage 1 as no responses were seen. A higher than expected occurrence of pneumonitis (Pn) occurred in both arms, higher in arm A. Results: Median age was 60yrs, 32 pts had prior CT, 20 pts had liver metastases. The most common drug related toxicities were fatigue, rash, anorexia, diarrhea, stomatitis, cough and pneumonitis; pulmonary effects appeared schedule related. (See results table below) Conclusions: Daily oral RAD001C has activity in MBC. The final results of this randomized Phase II trial will provide data to plan future breast cancer trials of RAD001C.

[Table: see text]

[Table: see text]
Phase I trial of SU014813 in patients (pts) with advanced solid malignancies
Authors: Fiedler W. M. , Giaccone G. , Lasch P. , Van der Horst I. , Brega N. M. , Raber S. , Shalinsky D. , Ljubmir V. , Bokemeyer C. , Boven E.
Published: March 2020

3521

Background: SU014813 is an oral multi-targeted small molecule RTK inhibitor of VEGFRs, PDGFRs, sKIT & FLT-3 at nM concentrations. This study was designed to determine the safety, PK, PD, & preliminary efficacy of SU014813. Methods: Cohorts of pts with (w/) relapsed or refractory solid tumors received oral SU014813 at 25, 50, 100, 150, 200, or 250 mg on a 4 wks on/1 wk off (4/1), or 100 or 150 mg on a continuous dose (CD) schedule. The MTD was defined as the highest dose at which 0 of 3 or 1 of 6 pts encountered DLT during Cycle 1. Primary study endpoints included safety & PK. Plasma VEGF receptor & ligand concentrations were measured by ELISA & antitumor activity was assessed by CT scan. Results: 77 pts (57 M, 20 F; mean age 54.3 yrs) w/ chemorefractory solid tumors (22 CRC, 12 NSCLC, 12 sarcoma, 6 RCC,25 other) were enrolled. The rate of grade 3/4 AEs increased at doses above 100 mg w/hypertension & fatigue occurring in 18 % & 12 % of pts, diarrhea (9%) & thrombocytopenia (5%). The MTD was determined to be 100 mg CD, which was well-tolerated w/ manageable G3 diarrhea (n=2/6). PK was generally dose-proportional; at 100 mg CD, Cmax = 255 ng/mL, Tmax = 3 h, C24h = 63 ng/mL. SU014813 decreased plasma VEGFR2 & R3 concentrations in a dose- dependent manner (50–200 mg doses) but rebounded off treatment (4/1 schedule). Plasma VEGF generally increased after treatment but effects were variable. Twelve pts had an objective response at =50 mg daily dose levels; 1 pt w/ RCC had CR (183 days [d]);11 pts had PR (2 RCC, 2 thymoma, 2 NSCLC, 1 CRC, 4 other)(median 235 d; range 35- 470); 14 pts had stable disease (SD; median 178 d, range 58–554). Seven other pts who did not meet RECIST response criteria had long disease stabilization (median 200 d; range 180 - 440). Conclusions: SU014813 has a manageable safety & tolerability profiles at the doses studied. The MTD & recommended Ph II dose were determined to be 100 mg CD, as SU014813 had linear PK, modulated plasma VEGF receptors consistent with RTK inhibition, & demonstrated encouraging preliminary activity w/ durable responses across several tumor types.

[Table: see text]
Phase I and DCE-MRI evaluation of CDP791, a di-Fab PEG conjugate that inhibits VEGFR2
Authors: Jayson G. C. , Ton C. , Parker G. J. , Jackson A. , Mullamitha S. , Zinkewich-Peotti K. , Felix R. , Soranson J. , Rolfe L.
Published: March 2020

3523

Background: VEGF inhibitors are of proven clinical value. However, very few drugs specifically inhibit VEGFR2. CDP791 is a di-Fab PEG conjugate that binds VEGFR2 with a Kd of 49pM. Methods: We performed a single site, open label, dose-escalation study of CDP791. Cohorts of patients received between 0.3 and 30 mg/kg every 3 weeks until disease progression. DCE-MRI was performed at each dose level. Results: Thirty-one patients with colorectal, ovarian or renal cancer or other tumors were treated. There was no observed dose limiting toxicity or maximum tolerated dose. At doses of 10mg/kg or above, 7/16 patients developed cutaneous hemangiomata that regressed upon drug withdrawal. Biopsy of these confirmed that CDP791 was co-located with unphosphorylated VEGFR2. DCE-MRI revealed a dose- dependent inhibition of tumor growth over 20 days post-treatment, although there was no measurable change in Ktrans, an indicator of blood flow and capillary permeability. Fourteen patients received extended treatment and 5 (with renal (x2), colorectal, endometrial cancer and melanoma) had stable disease after 6 cycles. Plasma concentrations of CDP791 >10mcg/mL were sustained across the 21-day cycle for doses 10mg/kg and above. Conclusions: CDP791 is a pure VEGFR2 antagonist that is well tolerated up to doses of 30mg/kg. The drug is mechanistically active, associated with hemangiomata and dose-level dependent inhibition of tumor growth but not with reduction in vascular permeability or blood flow on DCE-MRI. These data imply that the drug is active in patients but challenge our understanding of the regulation of tumor vascular permeability. In addition, they suggest that serial 3-dimensional measurements of short-term tumor growth patterns are a sensitive method to detect biological therapy-related tumor growth inhibition.

[Table: see text]
Phase 1 study of a focal adhesion kinase (FAK) inhibitor PF-00562271 in patients (pts) with advanced solid tumors
Authors: Siu L. L. , Burris H. A. , Mileshkin L. , Camidge D. R. , Rischin D. , Chen E. X. , Jones S. , Yin D. , Fingert H.
Published: March 2020

3527

Background: PF-00562271 is a potent ATP-competitive inhibitor of FAK and, to a lesser extent, Pyk2. FAK transduces signaling from integrins and growth factors to modulate multiple properties important in neoplasia, including tumor cell invasion, proliferation and survival. Structure-activity relationships and preclinical antitumor activity are reported (W.G. Roberts et al, Proc AACR, 2007). Methods: Phase 1 dose-escalation study of PF-00562271 given as twice daily oral doses in 21 day cycles. Endpoints included safety, tolerability, PK, PD (serial tumor biopsies) and antitumor activity. PD was also evaluated by tumor glucose metabolism using FDG-PET. Dose escalation was performed in sequential cohorts of 3–6 pts. Results: 32 pts received 5 mg up to 105 mg BID with demographics M:F = 10:22; median age 60 (range 38–80). Primary tumor sites: colorectal (10), breast (4), neuroendocrine (2), lung (2), gastric (2), SCC (2), ovary (2), others (8). A total of 136 cycles have been administered, median = 3.2, range = 1–10+. Adverse events (AEs) possibly related to PF-00562271 in over 10% of pts included nausea, vomiting, fatigue, anorexia, abdominal pain, diarrhea, headache, sensory neuropathy, rash, constipation, dizziness. AEs were generally CTC grades 1–2 and reversible. Cmax and AUC increased dose-dependently, and AUC accumulated over 6-fold by day 14. Doses over 15 mg BID produced steady-state plasma concentrations, exceeding target efficacious levels predicted from preclinical models. On day 14, PET scans in one pt demonstrated significant (46%) decline in SUV of metastatic ovarian carcinoma, associated with improved tumor-related symptoms. Nine pts tolerated over 3 cycles and another 4 pts continued treatment over 6 cycles with stable disease. At 105 mg BID, dose- limiting toxicities included nausea, vomiting, diarrhea. Conclusions: At the doses evaluated, PF-00562271 is tolerable with extended BID oral administration and exhibits favorable PK and PD. Additional dose and schedule evaluations continue, and updated clinical and biomarker results will be presented.

No significant financial relationships to disclose.
Application of pharmacodynamic assays in a phase Ia trial of Apo2L/TRAIL in patients with advanced tumors
Authors: Pan Y. , Xu R. , Peach M. , Huang C. , Branstetter D. , Durbin B. , Herbst R. , Eckhardt G. , Mendelson D. , Holland P.
Published: March 2020

3535

Background: Recombinant human (rh) Apo2L/TRAIL is a dual pro-poptotic receptor agonist (PARA) that induces apoptosis by binding to pro-apoptotic receptors DR4 and DR5, which recruit a death inducing signaling complex upon ligand binding. This results in activation of the effector caspase 3/7, that subsequently cleaves intracellular substrates to execute cellular apoptosis. A Phase1a trial is underway to evaluate the safety and tolerability of rhApo2L/TRAIL in patients with advanced tumors. The aim of this study was to develop and validate high-throughput pharmacodynamic assays to monitor rhApo2L/TRAIL activity in easily accessible patient samples such as serum. Methods: To monitor rhApo2L/TRAIL activity in patients, we optimized assays to measure the release of the apoptotic markers caspase 3/7, cytokeratin 18 (CK18), and genomic DNA (gDNA) in serum. Serum caspase 3/7 levels were monitored using the Caspase Glo kit, which generates a luminescent signal upon cleavage of a caspase 3/7 substrate; cleavage of the caspase substrate CK18 was measured using an optimized form of the M30 ELISA assay; gDNA was measured using a β-actin-specific TaqMan real-time PCR assay. Mice bearing Colo205 xenografts were treated with rhApo2L/TRAIL and sera were collected and assayed for apoptotic markers. Upon validating these assays, we monitored the levels of apoptotic markers in cancer patients who received rhApo2L/TRAIL. Results: We detected transient increases in apoptotic markers in mouse sera 8–24 hr after treatment with rhApo2L/TRAIL. This increase was dose-dependent and correlated with active caspase 3 detected by IHC in Colo205 tumors. In the phase Ia study, increases in serum caspase 3/7 and gDNA levels were observed in >50% of colorectal, lung and sarcoma patients evaluated. Preliminary analyses show the percentage of increase correlates using both analytes and is dose-dependent. Conclusions: These findings support the use of serum-based pharmacodynamic assays as a means to monitor rhApo2L/TRAIL activity in patients with advanced tumors. A complete analysis of all patient serum samples from the ongoing phase Ia trial will be reported.

No significant financial relationships to disclose.
Dual targeting of vascular endothelial growth factor (VEGF) with sorafenib and bevacizumab: Clinical and translational results
Authors: Azad N. S. , Annunziata C. , Barrett T. , Chen C. , Steinberg S. , Kwitkowski V. E. , McNally D. , Kotz H. , Minasian L. , Kohn E. C.
Published: March 2020

3542

Background: VEGF is a major mediator of angiogenesis in malignancy. We targeted the VEGF pathway in series by combining the VEGFR2/Raf kinase inhibitor sorafenib (S) with bevacizumab (B), a selective anti-VEGF antibody. We hypothesized that this combination would suppress angiogenesis and tumor growth, with corresponding changes in correlative dynamic imaging. Methods: Eligible pts had non-curable solid tumors, ECOG performance status 0–1, good end organ function, and no prior exposure to S or B. We enrolled pts at S 200 mg po BID and B 5 mg/kg IV q2weeks (dose level [DL] 1) and escalated each drug sequentially. The MTD was DL1; 24 additional pts were enrolled at this dose and randomized to single agent S (Arm 1) or B (Arm 2) for one month, then S+B thereafter. Serum samples for cytokine analysis, dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and 18FDG- PET scans were performed at 0, 2, and 6 weeks. DCE-MRI and PET scans measured vascular permeability (Ktrans) and metabolic activity (standardized uptake values [SUV]), respectively. The Wilcoxon signed rank test was used to evaluate the differences between the paired imaging values at the test time points in an exploratory fashion. Results: 7/38 pts (6/14 ovarian ca pts and 1/3 renal cell ca pts) had partial responses (8+-20 mo; median 15). Grade 3–4 toxicities included hypertension (10), proteinuria (2, DLT), and thrombocytopenia (1, DLT). Common grade 2 toxicities were hand-foot syndrome (18), fatigue (13), infection (13), and hypertension (12). DCE-MRI Ktrans decreased with S+B compared to baseline (p<0.03, both arms); no significant change occurred with either S or B treatment alone or between arms. No significant changes in PET SUV measurements occurred with treatment. Correlation of dynamic imaging parameters with response was not possible due to the limited patient numbers. Serial cytokine analysis is presently being performed and will be included at the time of presentation. Conclusions: S+B is active in solid tumors with manageable toxicity. DCE-MRI shows a decrease in vascular permeability with S+B treatment. A larger trial is necessary to evaluate if DCE-MRI changes can be predictive of response and is ongoing now in ovarian cancer.

No significant financial relationships to disclose.
AZD2171 in combination with various anticancer regimens: Follow-up results of a phase I multi-cohort study
Authors: Shields A. F. , Heath E. , DeLuca P. , Pilat M. , Wozniak A. , Gadgeel S. , Puchalski T. , Xu J. , Liu Q. , LoRusso P.
Published: March 2020

3544

Background: AZD2171 is an oral, highly potent and selective inhibitor of VEGF signaling. Recent trials have shown that combining a VEGF signaling inhibitor with certain chemotherapies provides clinical benefit in patients with breast, colorectal and non-small-cell lung cancers. AZD2171 was evaluated with various anticancer regimens in heavily pretreated patients with advanced solid tumors. Methods: Once-daily oral AZD2171 20 mg, 30 mg and 45 mg was given in combination with: (1) mFOLFOX6 every 2 weeks; (2) docetaxel 75 mg/m2 every 3 weeks; (3A) irinotecan 300 mg/m2 every 3 weeks; (3B) irinotecan as in 3A + cetuximab (400 mg/m2 loading dose, followed by 250 mg/m2 every week); or (4) pemetrexed 500 mg/m2 every 3 weeks. The novel study design allowed simultaneous evaluation of the safety and tolerability of these regimens with AZD2171. Secondary objectives include preliminary evaluation of potential pharmacokinetic (PK) interactions and efficacy (RECIST). Results: As of Nov 2006, 54 patients were evaluable for safety ( Table ). No unexpected toxicities were observed, and the safety profile of AZD2171 was similar to that observed in single-agent AZD2171 studies. Across all five treatment arms, common adverse events irrespective of causality included fatigue (n=46), diarrhea (n=45) and hypertension (n=21). Efficacy data were available for 39 patients, 24 of which were evaluable according to RECIST. A best overall objective tumor response of partial response (n=3) or stable disease (n=19) was observed ( Table ). AZD2171 did not appear to have a major effect on the PK profile of oxaliplatin, 5-FU, pemetrexed, irinotecan [SN38] and docetaxel. Steady-state PK parameter values of AZD2171 in this study are comparable with single-agent AZD2171 studies. Conclusion: In this group of heavily pretreated patients, combination treatment with AZD2171 and various anticancer regimens has been generally well tolerated, with no apparent PK interaction and encouraging preliminary evidence of antitumor activity.

[Table: see text]

No significant financial relationships to disclose.
Assessment of safety and drug-induced tumor necrosis with sunitinib in patients (pts) with unresectable hepatocellular carcinoma (HCC)
Authors: Faivre S. J. , Raymond E. , Douillard J. , Boucher E. , Lim H. Y. , Kim J. S. , Lanzalone S. , Lechuga M. J. , Sherman L. , Cheng A.
Published: March 2020

3546

Background: VEGFRs and PDGFRs play key roles in the proliferation of HCC and tumor angiogenesis. Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET and FLT3. This study reports the results of the first European/Asian, open-label, single-agent SU phase II study in pts with unresectable HCC. Methods: Key eligibility criteria include histologically confirmed measurable HCC; ECOG PS =1; Child-Pugh (CP)-A/-B; adequate organ function; and no brain metastases, ascites, or prior liver transplant. Pts receive SU at 50 mg/d for 4 wks every 6 wks (4/2 schedule). The primary endpoint is ORR by RECIST. Other assessments include safety (NCI CTCAE v3.0), PK and antitumor activity (tumor density, volumetric measurement of percent tumor necrosis [VMTN] and intratumor blood perfusion on monthly CT scan). Results: 37 pts (median 61 yrs [range 34–82]; male 92%; PS 0:1, 50%:44%; CP-A/-B, 84%/14%; 40.5% with prior local treatments) received a median of 2 cycles (range 1–7+) of SU. Grade 3–4 toxicities included thrombocytopenia (43%), neutropenia (24%), CNS symptoms (24%), asthenia (22%) and hemorrhage (14%). Grade 1–2 skin toxicity was frequently reported. Dose reductions were required in 27% of pts. Four pts developed grade 5 events including ascites, edema, bleeding, drowsiness and hepatic encephalopathy. Decreased tumor density was observed in 68% of pts and activity assessed by VMTN showed minor (<50%) and major (=50%) post-treatment tumor necrosis in 25% and 46% of pts, respectively. One confirmed PR and 39% SD (best confirmed response) have been achieved. Post-treatment tumor blood perfusion parameters (blood volume and blood flow), decreased by an average of 39% (range: 13–72%). Preliminary PK data do not suggest any differences in drug exposure between risk groups (CP-A or CP-B). Conclusions: Evidence of =50% tumor necrosis in 46% of pts receiving SU suggests outstanding antitumor activity. However, change in tumor size (RECIST) may be inappropriate as a primary endpoint to evaluate SU in patients with HCC. Initial safety findings indicate that further evaluation of SU in this pt population with improved pt selection and dose schedule modification is warranted.

[Table: see text]
Results of a phase I study of bevacizumab (BV), everolimus (EV), and erlotinib (E) in patients with advanced solid tumors
Authors: Bendell J. C. , George D. , Nixon A. , Yu D. , Petros W. , Beci R. , Arrowood C. , Lockamy D. , O’Neill M. , Hurwitz H.
Published: March 2020

3548

Background: BV inhibits vascular endothelial growth factor (VEGF). EV is an mTOR (mammalian target of rapamycin) inhibitor. E inhibits epidermal growth factor receptor (EGFR) tyrosine kinase. VEGF, mTOR, and EGFR inhibitors have anti-tumor and anti-angiogenesis effects alone and in combination in preclinical models. As a combination targeted therapy, we evaluated BV + EV + E in a phase I, pharmacokinetic (PK), biomarker study. Methods: Cycle length was 28 days. Doses: BV 10mg/kg IV q14d. EV 5mg PO QD, escalating to 10mg QD. Once the recommended phase II dose (RPTD) of BV + EV was reached, E was added, starting at 75 mg PO QD. DLT was defined as any treatment-related grade 4 heme or grade 3/4 non-heme event in Cycle 1. Results: 34 pts have been enrolled (18 F, 16 M), 28 evaluable for DLT, 24 for efficacy. Median age is 58y (range 29–73). Dose level 1 (BV 10mg/EV 5mg) had no DLT’s. Dose level 2 (BV 10mg/EV 10mg) had no DLT’s and the cohort was expanded to 13 evaluable pts. E (75mg) was added to BV 10mg/ EV 10mg. 2/6 patients had DLT (grade 3 mucositis and grade 3 rash). The doses were adjusted to BV 5mg/EV 5mg/E 75mg. 3 patients had no DLT and this dose is the MTD and RPTD for the 3-drug combination. 20 more patients are being enrolled at the RPTD for biomarker studies. Other grade ¾ toxicity included: nephrotic syndrome, cardiac ischemia, ventricular thrombus, portacath thrombosis, and bowel perforation. 2 patients had PR: 1 renal and 1 osteosarcoma. 16/24 pts had SD (10–112+ weeks). 5/6 patients with colorectal cancer (CRC) previously progressing on BV had SD (16+ - 112 weeks). One CRC patient had 19% radiologic decrease. Conclusions: BV + EV + E preliminary clinical activity (notably in refractory CRC) and class-related side effects were seen. The MTD is BV 5mg/kg IV q14d + EV 5mg PO QD + E 75mg PO QD. Updated data will be presented.

No significant financial relationships to disclose.
A phase I dose escalation trial of a daily oral CDK 4/6 inhibitor PD-0332991
Authors: O’Dwyer P. J. , LoRusso P. , DeMichele A. , Gupta V. , Barbi A. , Dials H. , Chen I. , Courtney R. , Wilner K. , Schwartz G. K.
Published: March 2020

3550

Background: PD-0332991 is a novel oral inhibitor of CDK 4/6, which is active against Rb positive tumors and has never before been tested in humans. A phase I dose escalation trial of PD-0332991 administered as a daily oral single agent was conducted to investigate safety, pharmacokinetics and pharmacodynamics in patients with advanced cancer. Methods: PD-0332991 was administered daily for 21 days in 28-day cycles (Schedule 3/1) to patients in successive dose escalating cohorts at doses from 25 mg to 150 mg QD. An alternative schedule of 14 days dosing in 21-day cycles (Schedule 2/1) was tested at 100 mg to 225 mg QD. Patients with advanced Rb positive solid tumors were enrolled in the study. Results: Fifty-seven patients have been enrolled into the study. The most common tumor types were: breast, colorectal, liposarcoma, and melanoma. The median age across the study was 57 years. For Schedule 3/1, the MTD/RP2D was determined to be 125 mg QD. For Schedule 2/1, the MTD/RP2D is still to be identified but the maximum administered dose (MAD) was determined to be 225 mg QD. Six DLTs have been observed, all relating to myelosuppression. The most common AEs were neutropenia, anemia, fatigue, nausea, constipation, vomiting and diarrhea. Concentrations were moderately variable (% CV range in AUC on Day 8 of Cycle 1 was 14–64%) with dose-dependent increases in exposure observed following PD-0332991 administration (mean AUC(0–10 hr) values were 724 and 1,500 ng.hr/mL at the 125 mg and 225 mg dose levels, respectively). The effect of food on PD-0332991 pharmacokinetics is currently being evaluated. In Schedule 3/1, there have been 6 patients with stable disease (= 10 cycles) with 3 patients (one each with breast cancer, colon cancer and ovarian cancer) with stable disease for at least 20 cycles. In Schedule 2/1, one patient has had stable disease for at least 10 cycles. Updated data will be presented. Conclusions: The principal and dose limiting toxicity of PD- 0332991 is myelosuppression. The RP2D for Schedule 3/1 is 125 mg QD. The MAD has been determined for Schedule 2/1 as 225 mg QD and the dose in this schedule has been de-escalated to 200 mg QD to evaluate the MTD. Tumor specimens, when available, from patients in both schedules are also being tested for pharmacodynamic modulation of phospho-RB protein.

No significant financial relationships to disclose.
Mechanism of bevacizumab-induced arterial hypertension: Relation with skin capillary rarefaction in patients treated for metastatic colorectal cancer
Authors: Morere J. F. , Des Guetz G. , Mourad J. , Lévy B. I. , Breau J.
Published: March 2020

3557

Background: Bevacizumab in combination with chemotherapy is the standard treatment of metastatic colorectal cancer (mCRC). Hypertension (HT) has been reported in all studies, in particular grade 3 HT (3 - 16%) (Saif and Mehra, 2006 Expert Opinion on Drug Safety). The mechanism underlying bevacizumab-related HT is not yet clearly understood and recent studies have demonstrated that humoral factors involving the renin-angiotensin system and the sympathetic nervous system had little role in the observed increase in BP. As far as microvascular rarefaction has been reported in all forms of human and experimental HT, we tested the hypothesis that anti VEGF therapy could induce microvascular rarefaction in non tumoral tissues and, thus, result in an increase in BP Methods: For 16 patients treated for mCRC, Bevacizumab was administered at 5 or 7.5 mg/kg every 2 or 3 weeks depending on the frequency of concomitant chemotherapies which were FOLFIRI (4 patients) or XELOX (12 patients) We used intravital video-microscopy to measure basal and maximal (during venous congestion) skin capillary densities in the dorsum of the fingers. Aortic stiffness was evaluated using pulse wave velocity, and microvascular endothelial function was assessed by laser-Doppler flowmetry combined with iontophoresis of three different doses of acetylcholine (ACh). All measurements were performed in 16 patients (mean age: 59±10 y) before and after a 6 month treatment with bevacizumab (mean cumulative dose: 3.16±0.90 g) Results: are summarized in the following table : Conclusions: Pharmacological blockage of VEGF receptors result in endothelial dysfunction and capillary rarefaction in humans. Both changes are closely associated with and seem responsible for the rise in blood pressure observed in patients receiving this treatment. This could be considered for future study about anti- angiogenic treatment and HT.

[Table: see text]

No significant financial relationships to disclose.
Evaluation of AZD2171, an oral, highly potent and selective VEGFR signaling inhibitor, in renal cell carcinoma (RCC): Combined results from two phase I studies
Authors: van Herpen C. , Drevs J. , van Cruijsen H. , Voest E. E. , Punt C. J. , Robertson J. , Saunders O. , Zirrgiebel U. , Unger C. , Giaccone G.
Published: March 2020

3560

Background: Antiangiogenic agents have recently demonstrated promising activity in patients with advanced RCC. AZD2171 is an oral, highly potent and selective inhibitor of VEGFR-1, -2 and -3 tyrosine kinases, and is currently in Phase II/III development in NSCLC and CRC. Safety and efficacy results are presented for patients with RCC who participated in two Phase I dose-escalation studies of AZD2171 in advanced solid tumors. Methods: Patients with advanced recurrent metastatic RCC received once-daily oral AZD2171, either as monotherapy (Drevs et al. Proc Am Soc Clin Oncol 2005: abst 3002; completed) or in combination with gefitinib (van Cruijsen et al. Proc Am Soc Clin Oncol 2006: abst 3017; ongoing). All patients had received prior interferon-a ± interleukin-2/ 5-FU or radiotherapy. Results: Twenty-one patients received AZD2171, 4 as monotherapy (20 mg, n=1; 60 mg, n=3) and 17 as combination therapy (AZD2171 20–45 mg with gefitinib 250 or 500 mg). The adverse event (AE) profile in RCC patients was similar to that reported previously for all patients in these studies; hypertension, dysphonia, nausea, vomiting, diarrhea and fatigue were the most common AEs. The most common CTC grade 3 AEs were hypertension (n=5) and diarrhea (n=4). Reductions in plasma levels of sVEGFR-2 were observed in RCC patients when AZD2171 was administered as a monotherapy or in combination with gefitinib; the reductions in the combination study were dose- and time-dependent (sustained). Nineteen patients were evaluable for efficacy (RECIST): 2/3 monotherapy patients experienced tumor regression, one of which was confirmed as a partial response (duration of response [DR] 87 days); in the combination study, 6/16 (38%) patients achieved a partial response (median DR 6 months; 3/6 ongoing at data cut off) and 7/16 (44%) patients had stable disease (4/7 had a confirmed 10–30% reduction in maximum tumor diameter). Conclusion: AZD2171, both as monotherapy and in combination with gefitinib, showed encouraging antitumor activity and a manageable toxicity profile in patients with advanced RCC who had failed prior therapy. A randomized Phase II investigation of AZD2171 monotherapy (45 mg/day) vs placebo in patients with advanced RCC is ongoing.

[Table: see text]
A phase I trial of RX-0201 (AKT anti-sense) in patients with an advanced cancer
Authors: Marshall J. , Posey J. , Hwang J. , Malik S. , Shen R. , Kazempour K. , White L. R. , Fraser K. M. , Chang C. G. , Ahn C. H.
Published: March 2020

3564

Background: Akt-1, a proto-oncogene, plays a vital role in cancer progression by stimulating proliferation and inhibiting apoptosis of cancer cells. RX-0201, a 20-mer oligonucleotide with sequence complementary to Akt-1 mRNA, is designed to inhibit the expression of Akt-1 within cancer cells in cancer patients (pts). Non-clinical studies conducted on RX-0201 demonstrated that RX-0201 bears significant in vitro and in vivo anti-cancer activities with favorable safety. Purposes: The aims of the current phase I trial were to determine the maximum tolerated dose (MTD) and to establish pharmacokinetic (PK) and safety profiles of RX-0201 in pts with an advanced cancer. Methods: RX-0201 was administered to pts with an advanced cancer by up to 2 cycles of continuous infusion; each cycle of infusion lasted for 14 days which was followed by a 7-day rest. Rapid dose escalation had been used until at least a grade (G) 2 toxicity was observed, and then a traditional dose escalation followed. Entry criteria included Karnofsky Performance Status score =70, advanced cancer, tumor accessible for paired biopsy, and signed informed consent. 17 pts were enrolled and treated at a dose level ranging from 6 to 315 mg/m2/d on D1–14, repeated q 21 d. Results: G 3 fatigue was observed in two pts at the 315 mg/m2/d dose; three pts dosed at 250 mg/m2/d were not noted with any G 3 toxicity, which make this dose (250 mg/m2/d) the recommended phase II trial dose. No other significant, compound-related, adverse events were observed in those 17 pts participated. Pts PK profiles of RX-0201 and AKT-1 immunohistochemistry results on pts’ tumor biopsy samples will also be presented. Conclusion: MTD of RX-0201 is 315 mg/m2/d in pts with an advanced cancer when the compound is administered in the current continuous infusion regimen.

No significant financial relationships to disclose.
A phase I trial of the heat shock protein 90 (HSP90) inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17- DMAG, alvespimycin) administered weekly
Authors: Pacey S. C. , Wilson R. , Walton M. , Eatock M. , Moreno-Farre J. , Gallerani E. , Davergne V. , Raynaud F. , Workman P. , Judson I.
Published: March 2020

3568

Background: The geldanamycin analogue 17-DMAG inhibits the ATPase activity of HSP90, thus altering client protein & chaperone interactions and targeting client proteins for degradation. The plethora of oncogenic HSP90 client proteins offers the potential of combinatorial blockade across multiple, cancer causing signalling pathways in cancer. Methods: 17-DMAG was administered weekly to patients with advanced, solid tumours using a dose-doubling 3 + 3 Phase I design. The pharmacokinetic (PK) and pharmacodynamic (PD) analyses undertaken were validated to comply with U.K clinical trial legislation. Results: 10 patients, 7 male and 3 female with a mean age of 60 years (range 38 - 78) have received 107 infusions (mean 10.7 weeks, range 2 - 30) at dose levels of 2.5mg/m2, 5mg/m2 & 20mg/m2. No dose-limiting or drug related grade 3 or 4 toxicity has occurred in 9 patients eligible for toxicity assessment. A linear relationship exists between dose and AUC and Cmax (see table ). Hsp72 induction and CDK4 depletion (consistent with HSP90 inhibition) have been detected at doses of 20mg/m2 in peripheral blood mononuclear cells. A confirmed partial response (by PSA and RECIST) has occurred in a patient with hormone refractory prostate cancer (HRPC). Conclusions: We have shown linear PK for 17-DMAG up to 20mg/m2. No dose-limiting toxicity has been encountered. A robust biologically active dose has not been reached but evidence of the pharmacological signature of HSP90 inhibition has been detected in surrogate tissue and a confirmed PR seen in a patient with HRPC. These data support dose escalation to 40mg/m2 and paired tumor biopsies will be taken to further define the PK-PD-clinical relationships.

[Table: see text]

[Table: see text]
A phase I safety and pharmacokinetic study of apomab, a human DR5 agonist antibody, in patients with advanced cancer
Authors: Camidge D. , Herbst R. S. , Gordon M. , Eckhardt S. , Kurzroc R. , Durbin B. , Ing J. , Ling J. , Sager J. , Mendelson D.
Published: March 2020

3582

Background: Apomab, a fully human affinity-matured IgG1 monoclonal antibody, is a DR5 pro-apoptotic receptor agonist that triggers the extrinsic pathway of apoptosis. DR5 is expressed both on malignant and normal cells; however, pre-clinical data indicate that DR5 activation stimulates apoptosis predominantly in malignant cells. This first-in-human study assessed the safety, pharmacokinetics (PK) and any early evidence of anti-cancer efficacy of Apomab. Methods: Patients with advanced treatment-refractory solid tumors received Apomab IV on Day1 (cycle 1 = 28 days, cycles 2–8 = 14 days) at 1, 4, 10, 15, or 20 mg/kg (stage 1); with cohort expansion at 10 mg/kg or the MTD (if lower) every 14 days (stage 2). Tumor assessments were made after 2, 4 and 8 cycles. Therapy continued past 2 cycles as permitted by on-going evidence of benefit, until disease progression or unacceptable toxicity occurred. Results: 26 patients ECOG PS â‰¤1 have been enrolled and treated through 20 mg/kg. The 20 (8M, 12F) with confirmed data (up to 15mg/kg) received a median of 2 cycles (range 1–8). All dose levels have been tolerable (<33% dose limiting (Grade 3 drug-related) toxicities in the first 2 doses + 24 hours). 2 disparate DLTs occurred among 11 patients treated at 10 mg/kg. 1 patient (ovarian cancer) had asymptomatic transaminitis (ALT and AST) at C1D5, reaching Grade 3 by D29, received no further Apomab with resolution by D53. 1 patient (colorectal cancer) had a pulmonary embolism C1D4. Six patients completed at least 4 cycles of Apomab, 4 completed 8 cycles. No objective responses have been seen but at 10 mg/kg 1 patient (appendiceal cancer) remains on study (stable disease) past 8 cycles and 1 patient (colorectal cancer) had 28% shrinkage of target lesions and symptomatic improvement after 4 cycles. PK of Apomab is dose-proportional at 1 and 4 mg/kg with a typical IgG1 half-life of ∼15–20 days. AUC/Css,min concentrations at >4 mg/kg are greater than those displaying activity in preclinical models. No HAHA responses have been seen to date. Conclusions: Apomab is well tolerated with a minor response seen in a colorectal cancer patient. Enrollment is continuing at 10mg/kg. Further safety and efficacy data will be presented.

No significant financial relationships to disclose.
Phase I clinical trial of CX-3543, a protein-rDNA quadruplex inhibitor
Authors: Papadopoulos K. P. , Northfelt D. W. , Hufnagel D. M. , Ricart A. D. , Griffin P. P. , Oslund M. D. , Von Hoff D. D. , Rice W. G. , Lim J. K. , Marschke R. F.
Published: March 2020

3585

Background: CX-3543 inhibits over-expressed ribosomal RNA synthesis in cancer cells by disrupting an essential protein-rDNA quadruplex complex, thereby inducing selective apoptosis. A phase I clinical trial for CX-3543 was undertaken to determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK) of this agent. Methods: Eligible patients with advanced solid tumors received CX-3543 in successive dose cohorts at: 10, 20, 40, 80, 160, 240, 360 and 480 mg/m2. Drug is administered by daily intravenous infusion on the first five consecutive days of a three week cycle, and the infusion duration has varied from one hour to six hours. Response by RECIST is determined after every 2 cycles. Results: Thirty-three patients (M/F:19/14; median age 69, range 44–83) with advanced solid tumors were treated with intravenous CX-3543. No drug related serious adverse events (SAEs) were encountered. DLTs of infusion-related cough and headache were identified at 480 mg/m2 (The MTD was 360 mg/m2). These adverse events were fully and rapidly reversible upon slowing or interrupting the infusion. Other drug-related adverse events were of mild to moderate intensity. Four patients had stable disease for longer than 4 months and one patient, with stable disease for over one year, currently continues on study. CX-3543 demonstrated an increasing plasma terminal half life at the higher dose levels due to a ‘reservoir‘ effect from CX-3543 reversibly binding to blood cells. Conclusions: CX-3543 administered as a 6 hour infusion for five consecutive days of a three week cycle is well tolerated and has stabilized disease in a number of patients enrolled in this phase I study. This trial is now in an expanded enrollment phase at 360 mg/m2 and pharmacodynamic measures, specifically FDG-PET scans and circulating tumor cells, have been included to detect biological activity at this dose level.

No significant financial relationships to disclose.
A phase I study of q3W R1507, a human monoclonal antibody IGF-1R antagonist in patients with advanced cancer
Authors: Rodon J. , Patnaik A. , Stein M. , Tolcher A. , Ng C. , Dias C. , Kurman M. , Greig G. , Kurzrock R. , Rubin E.
Published: March 2020

3590

Background: Insulin-like growth factor receptor (IGF-1R) is a tyrosine kinase cell surface receptor overexpressed in cancer cells which mediates the mitogenic and anti-apoptotic actions of IGF, playing a key role in malignant transformation. The safety and pharmacokinetics of 3-weekly administration of R1507, a human monoclonal antibody selective for IGF-1R, were explored in this phase I dose escalation study in patients with advanced solid tumors or lymphomas. Materials and Methods: Multiple ascending doses of R1507 were administered as a 1 hour infusion every 3 weeks until the development of dose-limiting toxicity (DLT) or progressive disease. Inclusion criteria: ECOG PS 0–1, adequate hematologic, hepatic, and renal function, CD4 count >200/μl. Exclusion criteria: infection, immunosuppressive agents, diabetes mellitus, uncontrolled systemic disease, NYHA III/IV CHF. DLT defined as ≥ grade 2 hypersensitivity reaction; ≥ grade 3 non-hematologic toxicity; ≥ grade 2 cardiac toxicity; ≥ grade 3 hematologic toxicity = 7 days, or dose delay > 1 week due to toxicity. Blood samples were collected following 1st dose for non compartmental PK analysis and for future analysis of IGF-1R levels. Results: 21 patients (pts) (M:F 14:7) were enrolled in 1 of 4 dose levels (dose range 1–16 mg/kg). Mean pt age 57 yrs (range: 30–81), mean prior treatments 4.6 (range: 1–9). Mean treatment cycles 2.6 (range: 1- 6). Six pts remain on study. Adverse events (AE) included infection (6 pts), fatigue (4); rash, fever, arthralgia, cough, diarrhoea, abdominal and back pain (3 each). No DLT or serious AEs attributed to study drug were reported. Activity: 10 pts showed stable disease (median 33 days). PK: Clearance (CL) decreased from 812 mL/Day (Coefficient of Variation [CV] =19.9%) in the 1 mg/kg group to 418 mL/Day (CV=46.7%) in the 16 mg/kg group; Volume of distribution was in the range of 4.4 - 5.4 L (CV=10.9–34.8%). T1/2 increased from 4 to 9 days. Conclusions: Treatment with R1507 is tolerable at the dose of 16mg/kg q3W. Treatment-related toxicities are mild and clinically manageable. Decrease in CL across doses levels suggests a saturable elimination pathway. T1/2 value of ∼8 days supports a weekly dosing for future trials.

[Table: see text]
Phase I and pharmacokinetic (PK) study of PTK787/ZK222584 (PTK/ZK) plus capecitabine (cape) in patients (Pts) with advanced cancer
Authors: Schilsky R. L. , Geary D. , Skoog L. , Desai A. , Valickas J. , Masson E. , Laurent D. , Pendowski C. , Vokes E. , Ratain M.
Published: March 2020

3595

Background: PTK/ZK is a small molecule inhibitor of the vascular endothelial growth factor receptor family. Cape is a standard treatment for pts with breast and colon cancer, tumors for which angiogenesis inhibition is beneficial. Therefore, we conducted a phase I study of the combination to determine the maximally tolerated doses (MTD), toxicities and PK interactions. Methods: Eligible pts had advanced cancer with no standard treatment option, Karnofsky performance status (KPS) > 70, and normal organ function. Pts with bone marrow or CNS involvement or who had more than 4 prior chemotherapy regimens were excluded. A dose escalation (dosesc) phase was conducted to determine the MTD followed by a dose expansion (dosexp) phase to assess PK interactions. PTK/ZK was given as a single oral daily doser without interruption and cape was given orally twice daily for 14 of 21 days. Results to Date: 43 pts (30 male, 13 female), median age 61 y (34–78 y) and median KPS 95 (70–100) were enrolled in the dosesc phase. 37 had prior chemotherapy; 5 had radiation only. Diagnoses included colorectal cancer (10), head/neck (7), sarcoma (5), renal (4), stomach/pancreas (3 each) and others (11). 29/43 pts were evaluable for MTD determination and received a total of 145 cycles. Doses of PTK/ZK-cape (mg-mg/m2) were: 750/2,500; 1,000/2,500; 750/2,000; 1,000/2,000; 1,250/2,000. DLT occurred in 1/6 pts (gr 3 fatigue) at 750/2,500; 2/2 pts (≥gr 3 fatigue, hypertension [HTN]) at 1,000/2,500; 0/3 pts at 750/2,000; 2/12 pts (≥ gr 3 dizziness, HTN and seizure) at 1,000/2,000 and in 1/6 (gr 3 proteinuria) pts at 1,250/2,000. 1,250 mg was the highest PTK/ZK dose planned. Other common toxicities in the dosesc phase were hand-foot syndrome (HFS, 93%) and HTN (28%). In the dosexp phase 26 pts (14 M, 12 F) have thus far received 73 cycles at the MTD (1,250/2,000). Median age is 65 y (26–79 y) and median KPS is 80 (70–100). 28/73 cycles were delayed or interrupted for toxicity with gr ≥3 toxicities (# cycles): HFS (7), fatigue (5), increased LFTs (5), HTN (3), DVT/PE (4). 23 pts (17 in dosesc and 6 in dosexp) had response or stable disease longer than 12 weeks. Final results and PK data will be presented. Conclusion: PTK/ZK and cape can be combined without unexpected toxicities.

No significant financial relationships to disclose.