bluuebunny/crossref_metadata_2025 huggingface dataset:
A first-in-human phase I study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID in patients with advanced solid tumors
Authors: Wagner A. J. , Von Hoff D. H. , LoRusso P. M. , Tibes R. , Mazina K. E. , Ware J. A. , Yan Y. , Derynck M. K. , Demetri G. D.
Published: August 2020

3501

Background: The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers. GDC-0941 is a potent and selective oral inhibitor of the class I PI3K with 3 nM IC50 for the p110-alpha subunit in vitro and 28 nM IC50 in a cell-based pAKT assay and demonstrates broad activity in breast, ovarian, lung, and prostate cancer models. Methods: A Phase I dose escalation study using a 3+3 design was initiated in patients (pts) with solid tumors. GDC-0941 was given on d1, followed by 1 wk washout to study single-dose PK and PD markers. GDC-0941 was then administered qd on a 3 wk on, 1 wk off, schedule. Steady-state PK and PD were evaluated after 1 wk of continuous dosing. A separate concurrent dose-escalation arm with bid dosing was initiated after the third qd cohort. Results: Nineteen pts have been enrolled in 5 successive dose-escalation cohorts in the qd arm with dose levels up to 80 mg daily. Seven pts were enrolled in 2 cohorts in the bid arm at total daily doses of 60 and 80 mg. The most frequently reported drug-related AEs were Grade 1/2 nausea, fatigue, diarrhea, peripheral edema, and dysgeusia; no drug related grade >3 events have been reported. PK data suggest dose-proportional increases in Cmax and AUC. Potential signs of anti-tumor activity have been observed with a soft tissue sarcoma pt on-study for >176 days with stable disease (30 mg qd), an ovarian cancer pt with an on-study 2.8-fold decrease in CA-125 response to normal levels (30 mg bid) and a pt with endometrial cancer with a decrease in tumor FDG-PET uptake (80 mg qd). Conclusions: GDC-0941 is generally well-tolerated with potential signs of anti-tumor activity. Preliminary PK data suggest dose-proportional increases in exposure over the dose levels evaluated. Dose-escalation on both the qd and bid schedules continues with updated data to be presented.

[Table: see text]
A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics of XL765, a PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with advanced solid tumors
Authors: LoRusso P. , Markman B. , Tabernero J. , Shazer R. , Nguyen L. , Heath E. , Patnaik A. , Papadopoulos K.
Published: August 2020

3502

Background: XL765 is a potent and selective inhibitor of Class I PI3K isoforms, TORC1, and TORC2. XL765 has shown dose-dependent target modulation and tumor growth inhibition or shrinkage in multiple human xenografts. Methods: Pts receive XL765 bid or qd for 28-day cycles. PK and pharmacodynamic analyses are performed. Tumor response is assessed by RECIST every 8 weeks. Results: To date, 34 pts have been dosed with XL765; 26 pts on a bid regimen (15–120mg) and 8 pts on a qd regimen (70–100 mg). Maximum administered doses are 120 mg bid and 100 mg qd. Dose-limiting toxicities (DLTs) occurred at 120 mg bid and 60 mg bid and included elevated hepatic transaminases (2), anorexia/hypophosphatemia (1), rash (1), and nausea/vomiting (1). Grade > 2 increase in transaminases, including one possibly related serious adverse event of Grade 4, occurred in 3 of 7 pts at 120 mg bid. Non-specific neurological complaints (1) and rash (1) were the DLTs that occurred at 100 mg qd. The most common (> 10% of pts) related adverse events were elevated liver enzymes, nausea and diarrhea. XL765 exposure increased with increasing doses (15–120 mg bid). Median tmax was 1–3 h post-dose. Mean t1/2,z ranged from 3 to 9 h at steady-state. Repeat dosing (bid or qd) resulted in moderate to no drug accumulation. XL765 augmented food-induced increases in plasma insulin, but not glucose, in an exposure-dependent fashion. Robust pharmacodynamic modulation of PI3K pathway signaling in PBMCs, hair follicles, skin, and tumors was evident following administration of XL765. These effects were exposure-dependent for some biomarkers in PBMCs and hair. Five pts had durable stable disease (> 3 months): appendiceal cancer (15 mg bid) 8 cycles; RCC (15 mg bid) 4 cycles; NSCLC (30 mg bid) 4 cycles; mesothelioma (60 mg bid) 10 cycles; CRC (100 mg qd) 6 cycles. Conclusions: In this phase I study, XL765 has exhibited potent pharmacodynamic activity at generally well tolerated doses. PI3K pathway inhibition of ∼60–90% in hair and skin was seen at multiple tolerable doses.

[Table: see text]
A phase I study of MK-2206, an oral potent allosteric Akt inhibitor (Akti), in patients (pts) with advanced solid tumor (ST)
Authors: Tolcher A. W. , Yap T. A. , Fearen I. , Taylor A. , Carpenter C. , Brunetto A. T. , Beeram M. , Papadopoulos K. , Yan L. , de Bono J.
Published: August 2020

3503

Background: Akt facilitates cell proliferation/survival and is a suspected driver of progression in ST. MK-2206, a highly selective non-ATP competitive allosteric Akti, has nM IC50 and broad preclinical antitumor activity. Methods: Safety and tolerability of MK-2206 administered QOD in 28-day cycles (cy) was assessed. Doses evaluated: 30, 60, 90 mg, and 75 mg. Main eligibility criteria: ≥18 yo, evaluable advanced ST, ECOG ≤1, HbA1c ≤8% or fasting glucose ≤110% upper limit of normal. PK and phosphorylated Akt (pAkt) in whole blood by meso-scale ELISA were measured. Sequential tumor biopsies were performed in a subset of pts. Results: Dose escalation occurred in 19 pts (8 female/11 male; median age 57 yo; ECOG 0/1: 5/14) and 37 cy of therapy with no DLTs at 30 and 60 mg. CTCAE G3/4 skin rash and CTCAE G3 mucositis were observed at 90 mg in 4/7 pts. After further accrual at 60 mg confirmed safety at this dose, 75 mg was explored; however, 2/3 pts experienced DLT of rash. Dose escalation is complete; the MTD of MK-2206 is 60 mg QOD. Common drug-related AEs included skin (47.1%), gastrointestinal (41.2%), and general disorders (29.4%). AUC0–48hr and Cmax were dose proportional up to 60 mg. Median Tmax is 6 hrs and mean t1/2 ranged from 63 to 76 hr. MK-2206 concentrations exceeding a preliminary, statistically determined PK target of approximately 50–65 nM for significant pAkti in blood were maintained over the entire dosing interval in all patients in the 60 mg cohort. Evidence of PD activity included decreases in whole blood pAkt at all dose levels, reversible CTCAE G1/2 hyperglycemia and CTCAE G1 insulin c-peptide elevations. RECIST stable disease following 2 cycles of therapy was observed in 1 pt at 30 mg and 5 pts at 60 mg. Observed clinical activity included: central tumor necrosis, decreased ascites and peripheral edema, reduction in index lesions, normalization of LFTs, and decreased CA-125. Conclusions: MK-2206 is generally well tolerated at doses up to 60 mg QOD with plasma concentrations that portend activity in preclinical models. PK/PD data suggest a substantial and maintained target inhibition at 60 mg.

[Table: see text]
Ongoing phase I studies of ABT-263: Mitigating Bcl-XL induced thrombocytopenia with lead-in and continuous dosing
Authors: Roberts A. W. , Wilson W. , Gandhi L. , O'Connor O. A. , Rudin C. M. , Brown J. R. , Xiong H. , Chiu Y. , Enschede S. , Krivoshik A. P.
Published: August 2020

3505

Background: ABT-263, a novel, oral BH3 mimetic, potently inhibits multiple antiapoptotic Bcl-2 family proteins. Ongoing phase 1 studies of ABT-263 show anti-tumor activity in CLL and some lymphomas (Wilson W et al, ASH. 2008). However, thrombocytopenia (TCP) due to on-target Bcl-XL inhibition-induced platelet apoptosis is also observed. Platelet nadir occurred on days 3–5 on 14/21 d dosing with each exposure to drug, was proportional to starting platelet count and recovered during therapy due to compensatory increased megakaryopoiesis. TCP was a dose limiting toxicity (DLT) in 3 patients (pts) in CLL study M06–873 (N = 15) where starting platelet counts tend to be low. We tested 2 strategies to mitigate variability in circulating platelet levels and achieve higher cumulative exposure: introducing a lower lead-in dose and using a continuous dosing (CD) (21/21 d schedule). Methods: CD with a 7 d lead-in dose was explored (150, 150 or 100 mg lead-in doses) with dosing at 200 and 275 mg, 225 and 325 mg, or 125 and 250 mg in studies M06–814 (NHL), M06–822 (SCLC), and M06 873 (CLL), respectively. Results: 22 pts on 21/21 d dosing enrolled to date in the 3 studies. Cmax & AUC at steady-state were comparable between pts at the same dose on 21/21 and 14/21 d schedules. Lead-in followed by CD appears to minimize platelet nadir and cycle variability. At 200 mg and grouping data from 200 and 225 mg doses, median platelet nadir in Cycle 1 was 46% and 42% of baseline on the CD schedule after lead-in vs 33% and 36% on the 14/21 schedule, respectively. For pts receiving 150 mg lead-in, nadir occurred during this phase, and platelet levels remained relatively stable on CD for doses up to 225 mg. 2 DLTs were observed for CD, 1 pt per study M06–814 (275 mg) and M06–873 (200 mg) experienced grade 4 (TCP). While CD enrollment and time on study is still limited, anti-tumor activity includes 1 unconfirmed partial response (68% CT regression) in a SLL pt at 275 mg and 3 CLL pts with ≥50% lymphocyte reduction for ≥2 months. Conclusions: Dosing schedule moderates early platelet nadir. Optimal dosing regimens may vary between tumor types especially where marrow infiltration is a feature.

[Table: see text]
First-in-human clinical, pharmacokinetic (PK), and pharmacodynamic (PD) phase I study of the first-in-class spliceosome inhibitor E7107 administered IV (bolus) on days 1, 8, and 15 every 28 days to patients with solid tumors
Authors: Eskens F. A. , Ramos F. J. , Burger H. , de Jonge M. J. , Wanders J. , Lopez-Anaya A. , Baselga J. , Tabernero J.
Published: August 2020

3508

Background: E7107 is a potent first-in-class inhibitor of the spliceosome, most likely by interacting with spliceosome-associated protein-130 (SAP 130). Splicing removes intron sequences from pre-mRNA and exons are fused resulting in the formation of mature mRNA. Alternative splicing frequently encodes oncoproteins. E7107 interferes the maturation process of pre-mRNA to mRNA, with consequent changes in protein expression profiles. Methods: Objectives of this study were to explore (1) tolerability and safety profile, (2) PK, (3) PD effects on pre-mRNA splicing, and (4) anti tumor activity of E7107 administered as bolus infusion on days 1, 8, 15 of a 28-day schedule Results: 36 patients (21M/15F, median age 61yrs (45–79)) received E7107 doses of 0.6 mg/m2 (n=4), 0.9 mg/m2 (n=3), 1.3 mg/m2 (n=3), 2.0 mg/m2 (n=3), 3.0 mg/m2 (n=4), 4.5 mg/m2 (n=3) and 4.0 mg/m2 (n=16). At 4.5 mg/m2 two episodes of DLT (grade 3 and 4 diarrhea) and at 4.0 mg/m2 one episode of DLT (a combination of grade 3 nausea, vomiting and abdominal cramps) were observed. Other frequently occurring side effects were mainly gastrointestinal. The maximum tolerable dose (MTD) is 4.0 mg/m2. No complete or partial responses were observed. Pharmacokinetic analysis revealed large volume of distribution (Vss: 279 to 1369 L), high systemic clearance (CL: 111 to 253 L/hr), and moderate elimination half-life (t1/2: 5.3 to 15.1 hr). Systemic exposure on Days 1 and 15 (Cmax, AUC0-∞) increased in a dose-dependent manner. At the MTD, mRNA levels of selected target genes (TRAPPC4, SLC25A19, GTF2H1), monitored in PBMC's, showed a 15–25-fold decrease, whereas unspliced pre-mRNA levels of DNAJB1 and EIF4A1 showed a 10–25-fold increase. Notably, at days 1 and 15, modulations generally peaked at 2–6 hr after end of the infusion and almost completely recovered to base-line levels at 24–48 hr. Conclusions: The MTD for E7107 using this schedule is 4.0 mg/m2. PK is dose-dependent and reproducible within subjects. PD analysis revealed dose-dependent reversible inhibition of pre-mRNA processing of target genes, confirming proof-of-principle activity of E7107.

[Table: see text]
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of HDM-2 antagonist JNJ-26854165 in patients with advanced refractory solid tumors
Authors: Tabernero J. , Dirix L. , Schoffski P. , Cervantes A. , Capdevila J. , Baselga J. , van Beijsterveldt L. , Winkler H. , Kraljevic S. , Zhuang S. H.
Published: August 2020

3514

Background: JNJ-26854165 is a novel first-in-clinic oral Human Double Minute-2 (HDM-2) ubiquitin ligase antagonist. It increases the level of HDM-2 client proteins (e.g. p53) by inhibiting the association of HDM-2-client protein complex with the proteosome. Preclinical studies have demonstrated potent anti-proliferative and apoptosis-inducing activity of JNJ-26854165 in a broad range of p53 wild type and mutant tumor models. Methods: A 3+3 dose escalation study with the primary objectives to determine the adverse event (AE) profile, dose limiting toxicities (DLT) and maximum tolerated dose of JNJ-26854165 is ongoing. Secondary objectives include evaluation of PK and PD activity. Eligible patients have ECOG PS≤2 and adequate hematological, renal and hepatic function. JNJ-26854165 is administered orally once daily on a continuous schedule (21-day cycles). Sequential skin and tumor biopsies are taken, and evaluations for HDM-2, p53 and other pathway related markers are performed, including further molecular analyses for HDM-2 activity. Results: 37 pts have been treated at 9 dose levels (DL), 4–300 mg qd. AEs included nausea, vomiting, fatigue, anorexia, insomnia, electrolyte disturbances, liver function tests and creatinine elevations, and asymptomatic QTc prolongation, mostly grade 1–2. A DLT, grade 3 QTcF prolongation, was observed in one patient at DL 9. The patient was asymptomatic and the QTc prolongation recovered after treatment discontinuation. PK data showed dose-proportionality. After dosing at 300 mg, steady state Cmax and AUC0–24h were 2–3 μg/mL and ≈50 μg.h/mL, respectively, well exceeding the expected effective exposure modeled by preclinical studies. PD data showed engagement of the targeted pathway such as dose-dependent p53 upregulation in skin, upregulation of HDM-2 levels in tumors after treatment, and an increase in plasma MIC-1 levels. No objective responses have been observed so far. Conclusions: JNJ-26854165 was well tolerated at doses beyond the expected effective exposure modeled by preclinical studies. PD activity was observed at the 150–300 mg dose levels. The trial continues with cohort expansion at 300 mg. Updated results will be presented.

[Table: see text]
An open-label, dose escalation, safety, and pharmacokinetic study of ENMD-2076 administered orally to patients with advanced cancer
Authors: Bastos B. R. , Diamond J. , Hansen R. , Gustafson D. , Arnott J. , Bray M. , Sidor C. , Messersmith W. , Shapiro G.
Published: August 2020

3520

Background: ENMD-2076, a novel, orally-active antimitotic and antiangiogenic molecule inhibits Aurora A as well as tyrosine kinases that drive tumor vascularization, including VEGFR2 (KDR), PDGFR and the FGF receptors. This Phase 1 study was designed to evaluate the safety, pharmacokinetics (PK) and preliminary efficacy of ENMD-2076 administered once daily to patients (pts) with advanced cancer. Methods: The dose escalation scheme utilizes 3 (or 4) + 3 (or 2) design. Pts receive ENMD-2076 once daily in 28-day cycles (followed by 7–14 days of rest between cycles 1 and cycle 2 only). Results: 14 pts have been enrolled in 3 dose cohorts (range 60 to 120 mg/m2/d). Median age/performance status is 62/1. The total number of treatment cycles to date is 45, with a median of 3 cycles (range <1 to 9 cycles). Most frequent, related toxicities (all grades, n=14) were hypertension (29%), fatigue (21%), proteinuria and diarrhea (both 14%). One pt experienced dose limiting toxicity of Grade 4 hypertension and Grade 3 cholecystitis in the first dose cohort of 60 mg/m2/d. Following drug interruption, the pt restarted at 30 mg/m2/d and continued for 4 additional cycles before being removed for progressive disease. Noncompartmental PK analysis of the first two dose levels shows that the plasma concentration of ENMD-981693 (the active free base of ENMD-2076) is dose- linear, as reflected in AUC and Cmax. The estimated terminal half-life (t1/2) is unaltered regardless of dose; however, t1/2 is approximately 50% greater at steady state than following single dose administration. Four ovarian cancer and 2 colon cancer pts have achieved decreases ranging from 11–61% in either CA125 or CEA, respectively (4 are associated with stable disease at Cycle 2 by modified RECIST criteria). Serum KDR concentrations assayed by ELISA decreased from baseline in all patients on treatment from a mean of 9153 pg/mL (SEM 464.2) at D1 to 6987 pg/mL (SEM 460.0) at D28 (p <0.05). Conclusions: ENMD-2076 is a small molecule kinase inhibitor with acceptable toxicity and preliminary evidence of antitumor activity in pts with ovarian and colorectal cancers.

[Table: see text]
Phase I study of vandetanib (V) and bevacizumab (B) combination therapy evaluating the VEGF and EGF signal transduction pathways in adults with solid tumors and NHL
Authors: Gutierrez M. , Murgo A. J. , Allen D. , Turkbey I. , Gardner E. R. , Trepel J. , Chen H. , Giaccone G. , Doroshow J. H. , Kummar S.
Published: August 2020

3522

Background: (V), a small molecule tyrosine kinase inhibitor, has strong inhibitory activity against VEGFR-2 and the EGF RTK. (B), a humanized anti-VEGF monoclonal antibody, blocks the binding of human VEGF to its receptors. We proposed that dual blockade of the VEGF pathway provides an added therapeutic effect compared with either agent alone. Methods: A standard 3–6 pt/cohort design, dose-escalation Phase I study was performed. (V) was self-administered PO, days 1–21 of each 21-day cycle. (B) was administered by IV infusion Q 3 wks. Objectives: Determine the toxicity profile and the MTD of the combination of (V+B); evaluate (V) pharmacokinetics, changes in tumor vascularity by dynamic contrast enhanced MRI (DCE-MRI) and effects of (V+B) treatment on circulating endothelial progenitors and mature circulating endothelial cells. Eligibility: ECOG ≤ 2, adequate organ function. The MTD is the dose level at which no more than 1 of 6 patients experience DLT during the first 2 cycles of treatment, and the dose below at which at least 2 (of ≤6) patients have DLT due to drug treatment. Results: 9 pts have been accrued to date. Diagnosis: pancreatic-1, NSCLC-1, colorectal-3, peritoneal mesothelioma-1, melanoma-1, NHL-1, jejunal adenocarcinoma (JAC)-1. 1 DLT (gr 3 Allergic reaction) was observed at DL 2. HTN was the most common toxicity at DL 2. Other gr 2–3 toxicities seen beyond 2 cycles included: diarrhea, elevated creatinine, leucopenia, anemia, thrombocytopenia, hemorrhage, prolonged QTc interval, proteinuria, rash (hand-foot syndrome / acneiform). Partial Response (PR) was achieved in 2 pts (pancreatic 14 mos + and JAC 6 mos); disease stabilization in 5 pts (4 mos +). DCE-MRI results showed a reduction in the parameters of permeability, (ktrans and kep), associated with one PR. Conclusions: We decided not to escalate beyond DL 2 due to the gr 2–3 toxicities observed with chronic therapy. We recommend (V): 200mg daily and (B): 5mg/kg IV q3 weeks as the Phase II dose.

[Table: see text]

No significant financial relationships to disclose.
Phase II trial of pharmacodynamically (PDally)-guided optimal biologic dose titration (OBDT) of sorafenib (S) in combination with metronomic cyclophosphamide (mC) in advanced neuroendocrine tumors (aNET)
Authors: Quintela-Fandino M. A. , Young A. , Webster S. , Grewal M. , Wang L. , Moore M. J. , Krzyzanowska M. , Mak T. W. , Siu L. L.
Published: August 2020

3526

Background: There is a paucity of reliable PD assays for guiding individual OBDT. PD effects of kinase inhibitors have been previously measured in static tissues. We developed a dynamic flow-cytometric PD assay that quantitates RAF signal transduction capacity (STC) based on the differential MEK´s phosphor-status in stimulated vs. basal conditions (phosphor-shift [PS]) in PBMCs. In a pilot study of 7 patients (pt) with advanced solid tumors in a phase I trial (unpublished data) the % of PS inhibition (I) 7 days after starting S at 400 mg BID showed a 10-fold interpatient variation and correlation with TTP. PDGFR-B/VEGFR2 blockade plus mC showed synergistic effect in the RIP1-Tag2 mouse NET model (J Clin Oncol. 23:939) In this phase II trial of aNET a double antiagniogenic strategy is undertaken: PD-guided OBDT of S + mC. Methods: Eligibility criteria included: unresectable NET with documented PD within 6 months prior to entry; ECOG 0–2; unlimited prior therapy but S; octreotide allowed. Therapy: pt start run-in phase with S at 200mg bid + 50 mg QD fixed dose of mC. After 7 d they escalate to 400 mg BID of S regardless of RAF STC assay results. RAF STC and toxicity are then assessed Q14d, escalating S at 200 mg BID increments until any of the following is achieved: a) 90% RAF STC I; b) maximum S dose of 800 mg BID; or c) intolerable Gr 2 or G3+ toxicity. Once S dose is determined based on these criteria, cycle 1 begins. Design: Simon 2-stage optimal; P0 = 0.05 P1 = 0.2; α =0.05 β = 0.1. Results: Accrual: 10 pt M:F = 6:4, islet cell:carcinoid = 5:5, age median 56 (40–79), ECOG 0:1 = 5:5. S doses (mg BID) at cycle 1 were 200 (2 pt)/400 (5)/600 (2)/800 (1); corresponding cycle 1 day 1RAF STC I (%) were 5, 53/94, 100, 95, 16, 65/25, 41/71, respectively (R2 = 0.13 p = 0.72) Most frequent Gr 3 non-hematologic possibly related adverse events in 30 cycles: hand-foot (2 pt), hypertension, abdominal pain, diarrhea, vomiting, lipase, ileal perforation (1 each). Disease control rate (9 evaluable pt): 78% (95% CI: 52–100%) (1PR, 6 SD). Conclusions: This approach appears feasible/safe. Large interpatient S dose differences are needed to achieve RAF SCT I/toxicity balance. No S dose-RAF SCT I relation is shown. Disease control rate is promising.

No significant financial relationships to disclose.
Phase I study of intravenous decitabine in combination with oral vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas (NHL)
Authors: Stathis A. , Hotte S. , Hirte H. , Chen E. X. , Webster S. , Iacobucci A. , McGill S. , Wang L. , Espinoza-Delgado I. , Siu L. L.
Published: August 2020

3528

Background: Decitabine (D), a hypomethylating agent, and vorinostat (V), a histone deacetylase inhibitor, belong to two different classes of drugs with an epigenetic effect. The ideal dose scheduling of these drugs remains controversial. This phase I study aims to determine the recommended phase II dose (RPTD) of the combination, their toxicity profile, pharmacokinetic (PK) interaction and preliminary clinical activity. Methods: Patients (pts) with advanced solid tumors or relapsed/refractory NHL are eligible. Two different schedules of D and V are being evaluated: sequential administration of D followed by V and concurrent administration of D and V. Dose escalation of D and V on the sequential schedule is described in Table. Results: To date, 27 pts have been entered into dose levels 1, -1, 1a, 1b, -1b, -2b of the sequential schedule. Demographics: median age 61 (range 31–76), F:M = 13:14, ECOG 0:1:2 = 8:16:3, tumor types: 24 solid tumor and 3 NHL. Pts received a total of 77 cycles with a median of 2 cycles (range 1–8). Adverse events (AE) of grade 3 or higher of at least possible attribution to the study treatment were neutropenia (16 pts), thrombocytopenia (4), febrile neutropenia (2), fatigue (2), and 1 pt each for constipation, dehydration, nasal bleeding, elevated alanine aminotransferase, and hyponatremia. Dose limiting toxicities (DLT) consisted mainly of myelosuppression, constitutional and gastrointestinal symptoms occurred in 7/27 (26%) of pts so far. Disease stabilization for 4 or more cycles was observed in 7 out of 22 (31.8%) evaluable pts (two with breast and one each of thymus, colon, pancreatic, appendix and non-small cell lung cancers). Conclusions: The sequential combination of D and V seems to be tolerable after some adjustments in the doses and duration of drug administration. Prolonged disease stabilization has been observed in multiple tumor types. Accrual is ongoing and RPTD will likely be dose level -1b or -2b. ( Supported by NCI Grant No. U01CA132123.)

[Table: see text]

No significant financial relationships to disclose.
A first-in-human phase I study of 4SC-201, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumors
Authors: Brunetto A. T. , Ang J. E. , Lal R. , Olmos D. , Frentzas S. , Mais A. , Hauns B. , Mollenhauer M. , Lahu G. , de Bono J. S.
Published: August 2020

3530

Background: 4SC-201 (former code BYK408740) is a specific, potent, pan-HDAC inhibitor with improved ADME properties. Methods: Patients (pts) with advanced refractory solid tumors were dosed once daily (QD) d1–5 in a 14-day cycle in sequential cohorts of 3–6 pts with 50 or 100% dose increments. Primary objectives were to determine safety, tolerability, pharmacokinetics (PK) and maximum tolerated dose (MTD) of 4SC-201. Pharmacodynamic assessment (histone acetylation and HDAC enzyme activity) and anti-tumor efficacy were secondary objectives. Blood samples for PK and PD were taken on days 1, 5 and 47 of treatment. Results: 18 pts (9M/9F) with a median age of 58.5 yrs (range 40–70) were treated at five dose levels: 3 pts each at 100mg, 200mg, 400mg and 600mg and 6 pts at 800mg. All pts were evaluable for toxicity and received at least 2 treatment cycles. Grade 3 DLT of nausea and vomiting occurred in 1 pt dosed at 800mg. Most common adverse events included nausea, vomiting and fatigue. 8 of 9 pts treated in the 600mg and 800mg cohorts had stable disease during the main phase of the study (4 treatment cycles). A patient with liposarcoma and another with thymoma (marginal response) continued treatment beyond 6 months. PK parameters were dose-proportional with a low inter-individual variability and indicated good bioavailability. The apparent t1/2 of oral 4SC-201 ranged from 2.3 to 4.4 hours. The degree of HDAC inhibition measured in a peripheral blood mononuclear cell functional assay was dose- dependent and increased from 50 to 100 %, although histone H4 acetylation accumulation after dosing did not differ significantly between dose levels. Conclusions: Oral 4SC-201 has favorable disposition and can be safely administered; 600mg QD d1–5 in a 14-day cycle is recommended for phase II evaluation. Safely administered doses modulate target with antitumor activity.

[Table: see text]
A phase I trial of the HSP90 inhibitor, alvespimycin (17-DMAG) administered weekly, intravenously, to patients with advanced, solid tumours
Authors: Pacey S. C. , Wilson R. , Walton M. , Eatock M. , Zetterlund A. , Arkenau H. , Beecham R. , Raynaud F. , Workman P. , Judson I.
Published: August 2020

3534

Background: alvespimycin (17-dimethylaminoethylamino-17-demethoxygeldanamycin, 17-DMAG) inhibits N-terminal ATPase activity of Heat Shock Protein 90 (HSP90). Chaperone interactions are altered such that client proteins are targeted for degradation. The plethora of HSP90 client proteins offers the potential of simultaneous blockade across multiple, oncogenic signalling pathways. Methods: the maximum tolerated dose, at which ≤ 1/6 patients experienced dose limiting toxicity (DLT) was determined by dose-doubling (3+3) design. PK and PD biomarker data were used to define a biologically effective dose (BED). PK (LC/MS/MS) and PD (western blot) assays were validated and compliant with European clinical trial legislation. Cancer Research UK and the NCI were co-sponsors. Results: twenty five patients, median age 58 (range 38–78) years, received 475 infusions at doses between 2.5 and 106 mg/m2. Dose doubling was possible to 80mg/m2 when grade 2 toxicity, including dry eye and blurred vision (2/5 patients) occurred. At 106mg/m2 DLT were observed (grade 3 fatigue, diarrhoea, dehydration and grade 4 hypotension, AST rise) in 2/4 patients, one patient died from cardiac arrest. PK data were as follows; plasma t = 24.6 ± 8.6 hr, Vss 468 ± 383 L (mean ± SD) and clearance 27.7 L/hr (range 8.26 - 153). Maximum plasma concentration increased proportionally with alvespimycin dose, area under the curve was only linear ≤ 80 mg/m2. PD changes (HSP72 induction) in peripheral blood mononuclear cells were detected ≥ 20 mg/m2. HSP90 inhibition (client protein depletion and HSP72 induction) was not readily detected until 106 mg/m2. Tumour samples confirmed HSP90 inhibition 24 hours after 17-DMAG in 1/1 and 2/4 patients given 106 and 80 mg/m2, respectively. Two partial responses one, confirmed, in a patient with hormone refractory prostate cancer and one, investigator assessed, in a patient with melanoma occurred. Both remain on study after 27 and 18 months, respectively. Nine patients (36%) have been on trial ≥16 weeks. Conclusions: The recommended phase II dose of alvespimycin is 80 mg/m2 weekly. PK and PD data support this as a BED.

No significant financial relationships to disclose.
A phase I study evaluating the pharmacokinetics (PK) and pharmacodynamics (PD) of the oral pan-phosphoinositide-3 kinase (PI3K) inhibitor GDC-0941
Authors: Sarker D. , Kristeleit R. , Mazina K. E. , Ware J. A. , Yan Y. , Dresser M. , Derynck M. K. , De-Bono J.
Published: August 2020

3538

Background: The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers. GDC-0941 is a potent and selective oral inhibitor of class I PI3K and demonstrates activity in a broad range of preclinical models (breast, ovarian, lung, and prostate). Methods: Patients (pts) with histologically confirmed advanced solid tumors and ECOG PS 0–1 were treated with GDC-0941 using a 3+3 escalation design at a single institution. Treatment was a single dose with 1wk washout, followed by GDC-0941 qd on a 3wk on, 1wk off schedule. Objectives were to determine MTD and DLT, evaluate PD endpoints in surrogate (pAKT in platelet rich plasma) and tumor (pAKT and pS6 in paired tumor biopsies and FDG uptake via PET imaging) tissues, and describe anti-tumor activity. Results: Thirteen patients have been enrolled in 4 successive cohorts (15–60 mg qd). GDC-0941 was generally well-tolerated with no drug related Grade 3 or 4 AEs or DLTs to date. Grade 1 diarrhea, nausea, dysgeusia, peripheral sensory neuropathy, dry mouth, thrombocytopenia, and increased aspartate aminotransferase have been observed. Preliminary PK data suggest dose-proportional increases in fasting mean Cmax and AUC. Preliminary PD data show decreased levels of pAKT in platelet rich plasma correlated with GDC-0941 plasma concentrations. GDC-0941 effects on FDG-PET imaging is being assessed, with 1 patient with HER2+ metastatic breast cancer showing a reduction in FDG uptake and improvement of a chest wall lesion (dose level 60 mg qd). Evaluation of PI3K pathway modulation from paired tumor biopsies is underway. Conclusions: GDC-0941 is generally well tolerated when administered qd at doses associated with inhibition of pAKT in surrogate tissues. Evidence of PD activity in tumor tissue has also been observed. Dose-escalation continues and updated PK/PD data will be presented.

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Phase I and pharmacokinetic (PK) study of dasatinib (D) and cetuximab (C) in patients (pts) with advanced solid malignancies
Authors: Feinstein T. M. , Agrawal S. , Stoller R. G. , Egorin M. J. , Argiris A.
Published: August 2020

3540

Background: D is a small molecule inhibitor of several kinases, including SRC. SRC can potentiate Epidermal Growth Factor Receptor (EGFR) signaling and is implicated in resistance to EGFR inhibitors. Combined inhibition of EGFR and SRC may lead to improved therapeutic effect. We evaluated the combination of D and C, a chimeric IgG1 monoclonal anti-EGFR antibody. Methods: Eligible pts had advanced solid malignancies treated with any number of prior regimens but without EGFR or SRC inhibitors, ECOG performance status 0–2, QTc interval on baseline EKG <450 msec, and adequate laboratory parameters. C was administered i.v as a loading dose of 400 mg/m2 on cycle 1, day 1 and then weekly at 250 mg/m2 on days 1, 8 and 15. D was administered orally, once daily, on a continuous schedule, on days 1–21. We used a standard up-and-down dose escalation scheme to assign pts on 3 dose levels (DL): 1- 100 mg QD, 2- 150 mg, 3- 200 mg. PK studies of D were performed on days 0 (prior to starting C) and 15 of cycle 1. Results: 25 pts (DL 1, 3 pts; DL 2; 19 pts; DL 3; 3 pts) were enrolled; 15 male; median age 62; median prior regimens: 2 (range: 0–5). Pts received a median of 2 cycles of D plus C (range: 1–15). 3 pts developed dose-limiting toxicities (DLT): 1 at DL 2 (headache; HA) and 2 at DL 3 (HA and nausea). Thus, MTD was reached at DL 2. DL 2 was expanded by an additional 12 pts to obtain further clinical and PK data. PK parameters (AUC and T-1/2) of D were comparable when given alone or in combination with C. Grade 3–4 toxicities in > 2 pts included: dyspnea (4), vomiting (4), nausea (3), allergic reactions (3), HA (3) and anemia (3). 21 pts developed HA (grade 1, 8 pts; grade 2, 10 pts). HA occurred after the loading of C, and took a median of 2 days to resolve. Pleural effusion developed in 4 pts (grade 2, 3 pts; grade 3, 1 pt) after 2–5 months of treatment. In 17 evaluable pts, there were no objective responses; 9 pts had stable disease: salivary gland cancer (3), thyroid (2), sarcoma (1), unknown primary (1), esophagus (1), and NSCLC (1). Conclusions: D 150 mg plus C was well tolerated, but early-onset HA was frequent. C administration did not affect D PK. We plan to treat 6 additional pts starting D 3 days after the C loading dose in an attempt to ameliorate early-onset HA. A phase II trial of C plus D in head and neck cancer is planned.

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Phase I evaluation of lapatinib and everolimus in patients with advanced malignancies: Southwest Oncology Group trial S0528
Authors: Hoban C. J. , Hoering A. , Synold T. W. , Chung V. , Gandara D. R. , Schott A. F. , Kingsbury L. , Lew D. , LoRusso P. M. , Gadgeel S. M.
Published: August 2020

3553

Background: Anti-tumor activity of Her inhibitors including lapatinib, an oral inhibitor of Her1 and Her 2, appears to correlate with their ability to down regulate PI3/Akt pathway. Everolimus, an oral inhibitor of mTOR, a serine/threonine kinase downstream of Akt, has shown enhanced efficacy when combined with Her inhibitors in pre-clinical studies. This phase I study is being conducted to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of the combination of lapatinib and everolimus. Methods: Pts with advanced tumors, for which there was no effective therapy, were eligible. The study consists of two parts. In Part I dose escalation to define MTD was performed with both drugs being given together. MTD was defined by dose limiting toxicities (DLT) in the first cycle (each cycle is of 4 weeks duration). In Part II, PK of both drugs are being analyzed in patients treated at MTD and randomized to either cohort A- everolimus alone for a week followed by both drugs, or cohort B- lapatinib alone for a week followed by both drugs. 12 PK eligible pts will be accrued to each cohort to detect the influence of one drug over the other drug's PK. Results: 26 pts were enrolled in Part I of the study, 23 were evaluable for DLT. Median age- 63 (29–76); males/females- 20/6. Common tumors were breast (4), lung cancer (3), adenoid cystic (3). 79 cycles (median 2, range 1–15) have been administered to date. 6 pts developed DLTs: pneumonitis, rash, diarrhea, stomatitis (2), and fatigue (2). The MTD of the combination is lapatinib 1250mg and everolimus 5mg, daily. None of the pts had a response but 11 pts (2 liver, 1 breast, 1 renal, 1 sarcoma, 2 adenoid cystic, 1 melanoma, 1 bladder, 1 NSCLC, 1 colorectal) had stable disease for 8 weeks or longer. Conclusions: The MTD of the combination is lapatinib 1250 mg and everolimus 5 mg. The dose limiting toxicities observed were diarrhea, stomatitis and fatigue. Accrual to Part II is ongoing and pharmacokinetic analysis is pending.

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TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies: A phase I/II dose finding and biomarker study
Authors: Angevin E. , Lopez J. A. , Pande A. , Moldovan C. , Shi M. , Soria J. C. , Wang X. , Harzstark A. , Saro J. , Escudier B.
Published: August 2020

3563

Background: TKI258 is a potent receptor tyrosine kinase inhibitor (TKI) that selectively targets VEGFR, PDGFR, FGFR, CSF1R, c-KIT, RET, TrKA, and FLT3. Compared to other TKI agents, TKI258 additionally targets FGFR. FGF has been reported as an important escape mechanism of anti-VEGFR therapies. Methods: The primary objective of this phase I was to determine the maximum tolerated dose (MTD) of TKI258, administered orally on a 5 days on / 2 days off schedule in repeated 28 day cycles, in mRCC pts refractory to standard therapies. A two-parameter Bayesian logistic regression model and safety data for at least 21 pts will be used to determine MTD. Results: A phase I study is ongoing. As of December 2008, 11 pts (9 m, 2 f), median age: 55 (29–66 yrs) have been enrolled. Four pts have been treated at 500 mg/day (start dose): 2 are ongoing at cycle (C) 7; 1 pt discontinued due to PD and 1 due to sinus bradycardia. Five pts received 600 mg/day: 2 DLTs (G4 hypertension and G3 fatigue - pts discontinued) leading to dose reduction of all patients to 500mg/day; 2 pts in C5 and C4, 1 pt discontinued for PD. Two pts just entered the extension cohort at 500 mg. Other toxicities ≥G2 included fatigue, nausea, vomiting, diarrhea, neutropenia, folliculitis and dizziness. PK data showed CMax range (180–487 ng/mL, n = 8), and AUC range (2200–8251 ng/mL*h). Preliminary biomarker data indicated pts had high baseline VEGF (506 ± 203 pg/ml, n=6) and bFGF (220 ± 185 pg/ml, n = 6) levels, which may reflect failure of previous anti-VEGF agents. Induction of plasma FGF23 levels, a pharmacodynamic biomarker of FGFR1 inhibition, was observed in pts from the first 500 mg/day dosing cohort. Preliminary evidence of efficacy is observed with one minor response (-17% at C4), 4 stable disease and 1 dramatic shrinkage/necrosis of some target lesions (lymph node & suprarenal mass). Conclusions: TKI258 500mg/day seems a feasible schedule in heavily pre-treated mRCC patients with some indications of clinical benefit. These preliminary findings will be confirmed in the extension cohort.

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Phase I evaluation of orally-administered CYT997, a novel cytotoxic vascular-disrupting agent, in patients with advanced cancer
Authors: Francesconi A. , Kotasek D. , Burge M. , Smith G. , Lickliter J.
Published: August 2020

3568

Background: CYT997 is a novel, small-molecule vascular disrupting agent which binds tubulin and inhibits microtubule assembly. The compound demonstrates potent antitumour and vascular-disrupting activity in preclinical models. A phase I study of CYT997 given by intravenous infusion showed favourable safety and tolerability, pharmacokinetics and preliminary evidence of pharmacodynamic activity. Unlike most other VDAs, CYT997 is orally available and a phase I dose-ranging study with oral capsule dosing is underway. Methods: CYT997 was administered orally every 2 weeks to patients with advanced solid tumours. Doses were escalated using an accelerated phase I design to cohort 6 and thereafter with a standard 3+3 design. Pharmacodynamic effects on tumour vasculature were assessed with DCE-MRI scans, circulating endothelial cell (CEC) assays and von Willebrand factor (vWF) plasma levels. Results: 21 patients (M/F: 16/5; median age 63, range 48–77) have been treated on study. A total of 56 cycles of CYT997 have been administered (median 2/patient, range 1–7) over 8 dose levels (15 - 164 mg/m2). Doses up to 118 mg/m2 were well tolerated. However, dose-limiting toxicities were observed at 164 mg/m2, consisting of grade 3 hypoxia in one patient and grade 3–4 asthenia in two patients. The grade 3 hypoxia was reversible. PK profiles revealed favourable oral absorption which was generally dose-linear. DCE-MRI assessments indicating significant changes in tumour Ktrans values consistent with vascular disruption were observed in 6 of 10 currently evaluated patients. No objective tumour responses were seen; however, disease stabilisation for six weeks or greater was observed in 13 patients. vWf and CEC analysis is currently ongoing. Conclusions: Orally-administered CYT997 is well tolerated at doses associated with vascular targeting activity. Moreover, its good oral bioavailability suggests the potential for novel administration schedules, including metronomic dosing.

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Phase I trial of NPI-2358 (a novel vascular disrupting agent) plus docetaxel
Authors: Millward M. , Mita A. , Spear M. A. , Federico K. C. , Lloyd G. K. , Cropp G. , Mita M. , Mainwaring P.
Published: August 2020

3571

Background: NPI-2358 is a vascular disrupting agent (VDA) that destabilizes tumor vascular endothelial cell architecture resulting in selective collapse of established tumor vasculature. In murine tumor models NPI-2358 produces tumor regression alone and synergistically with agents such as paclitaxel, docetaxel (TXT) and irinotecan, often with decreased toxicity. Methods: The objective was to determine the Recommended Phase 2 Dose (RP2D) of NPI-2358 in combination with TXT. Patients with previously treated advanced NSCLC or other malignancies where TXT use was appropriate were enrolled. Patients received 75 mg/m2 TXT every 21 days. NPI-2358 was administered IV 2 hours after TXT on Day 1, and alone on Day 8. The dose of NPI-2358 was escalated from the single agent biologic effect dose (BED) of 13.5 mg/m2 to the single agent RP2D of 30 mg/m2 using a 3+3 design. PK was assessed on Days 1 and 8. Results: 13 patients were enrolled of whom 10 had NSCLC. At all dose levels adverse events were consistent with those of both agents given alone. Adverse events commonly associated with NPI-2358 were seen, including nausea, vomiting, fatigue, fever, tumor pain and transient blood pressure elevations. One DLT of nausea, vomiting, dehydration and neutropenia occurred at 30mg/m2. PK analysis did not indicate a drug-drug interaction. Of the patients with NSCLC, 8 had measureable disease of which 2 demonstrated a partial response (PR), with 4 others having lesser regressions. The RP2D was thus 30 mg/m2 of NPI-2358 with 75 mg/m2 TXT. Conclusions: The combination of full dose NPI-2358 and TXT is tolerable. Although a limited data set, activity appears favorable relative to the 5–10% response rate reported with TXT alone in this population. Based on these results, efficacy is now being assessed in Phase 2 (the ADVANCE study), a randomized comparison of TXT ± 30 mg/m2 of NPI-2358 in 2nd- line NSCLC. Of note, entry criteria allow patients with squamous cell carcinoma, as VDAs do not appear to result in unfavorable outcomes associated with some other agents in this sub-population.

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A phase Ib trial of Bcl-2 inhibitor obatoclax in combination with carboplatin and etoposide for previously untreated patients with extensive-stage small cell lung cancer (ES-SCLC)
Authors: Chiappori A. , Schreeder M. T. , Moezi M. M. , Stephenson J. , Blakely J. L. , Salgia R. , Chu Q. S. , Malik S. M. , Modiano M. M. , Berger M. S.
Published: August 2020

3576

Background: Obatoclax (Ob) is a small-molecule antagonist of all the Bcl-2 prosurvival proteins. In vitro it enhances the effects of the drugs cisplatin and etoposide. Bcl-2 family proteins are frequently expressed in SCLC, and SCLC cell lines are sensitive to Ob. Methods: This study was designed to find the maximal tolerated doses (MTD) of oOb when given on a 21 day (D) cycle together with carboplatin (AUC 5 D1) and etoposide (100 mg/m2 D1–3), in separate dose escalations using Ob as a 3-hr infusion D1–3 and as a 24-hr infusion D1–3. Eligible patients had ES-SCLC, measurable disease, ≤1 prior therapy, ECOG PS ≤1, and adequate hematological, renal and hepatic function. 3- 6 patients were enrolled into ascending dose cohorts with standard DLT rules evaluating safety in C1 to determine dose escalation. Results: 24 patients were enrolled into 5 dosing cohorts (14 males; median age 67). A total of 66 cycles (C) have been administered to date. There were no DLTs in the initial cohorts using Ob 15 mg over 3 hr or Ob 30 mg over 24 hr. Two DLTs occurred in the Ob 30 mg over 3 hr cohort - both due to myelosuppression in previously treated patients. As a result, the trial was amended to exclude previously treated patients. 5 previously untreated patients receiving Ob 30 over 3 hr had no DLTs. There were no DLTs in the Ob 45 mg over 24 hr cohort but 2 patients in the Ob 24-hr infusion cohorts had infusion pump malfunctions while at home. There were 2 DLTs in the Ob 45 mg over 3 hr cohort (somnolence, euphoria, & disorientation) establishing MTD of Ob 30 mg over 3 hr daily x 3. After C2 the 6 previously untreated patients on Ob 24-hr infusion cohorts had 3 PRs, 1 SD, 1 PD, and 1 Unk; the 2 previously treated patients had PRs. After C2 all 7 previously-untreated patients at 15 or 30 mg in the 3-hr infusion cohorts have PR; the 3 previously treated patients had SD. Conclusions: Ob can be combined with carboplatin and etoposide using either a 3-hr or a 24-hr infusion, and both regimens are associated with high early response rates in ES-SCLC, perhaps due to inhibition of mcl-1. Due to practical issues with the 24-hr infusion arm, the 3-hr 30 mg MTD dose will be utilized in a randomized phase II versus carboplatin and etoposide alone.

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AT-101 or placebo (P) with docetaxel (D) in second-line NSCLC with gene signature biomarker development
Authors: Ready N. , Potti A. , Karaseva N. , Orlov S. , Luft A. , Popovych O. , Liu P. Y. , Holmlund J. T. , Wood B. A. , Leopold L.
Published: August 2020

3577

Background: AT-101 inhibits the Bcl-2 protein family (Bcl-2, Bcl-xL, Mcl-1, Bcl-W) with broad preclinical activity including synergy with D. Methods: We conducted a randomized, double-blind, P-controlled phase 2 study. Patients had received 1 prior chemotherapy regimen for advanced NSCLC. Patients received AT-101 (40 mg b.i.d. days 1–3) or P with D (75 mg/m2 day 1) Q 21 days. Primary endpoint was progression-free survival (PFS) by independent review (IR). Secondary endpoints were overall survival (OS) and investigator determined PFS. 102 patients were planned for 70 events (80% power, HR 0.6, 1-sided alpha 0.1). A biomarker of AT-101 activity was developed by treating 55 NSCLC cell lines with AT-101 and using the corresponding gene expression data to identify a genomic predictor of sensitivity to AT-101. Results: 106 patients were randomized. Baseline factors were balanced. Median OS for patients on AT-101+D was 7.3 months versus 5.6 months for P + D arm (HR 0.60, p = 0.05). The median investigator determined PFS was 12.6 weeks and 10.7 weeks for AT-101+D and P+D arms respectively (HR 1.0, p = 0.49); IR is ongoing. Common adverse events were fatigue (18%), anemia (18%), and dyspnea (18%). Grade 1/2 headaches occurred more frequently in the AT-101 arm. Analysis of gene expression data by Bayesian regression revealed a robust 500 gene predictor of sensitivity to AT-101 that was cross validated in a leave one out analysis and in an independent cohort of 32 NSCLC cell lines. Validation of the predictor in patient samples from the trial is ongoing. Conclusions: In this phase II trial AT-101, an oral pan Bcl-2 family inhibitor, had favorable OS compared to placebo when combined with docetaxel in previously treated NSCLC and was well tolerated. A genomic predictor of AT-101 sensitivity is likely to enrich for responders and identify novel therapeutic combinations for future

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