bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of high-dose methotrexate with rituximab versus other treatment regimens for primary central nervous system (CNS) lymphoma.
Authors: Lindhorst Scott Michael , McSherry Frances , Desjardins Annick , Friedman Henry S. , Peters Katherine B.
Published: March 2020

2090

Background: The most effective and least toxic treatment regimen for primary CNS lymphoma is a matter of debate. Most current regimens utilize various doses of high-dose methotrexate combined with other agents. The utility of deferred radiation is also under study. Methods: We evaluated 28 patients with primary CNS lymphoma treated with methotrexate 3.5 g/m2 and rituximab, as well as alternative regimens. Median, 12-month, and 24-month survival were compared for the various treatment regimens, as well as for patients who received radiation and those who did not. Results: Survival rates were significantly better in the methotrexate-rituximab treatment cohort than the other regimens examined (Log-Rank p-value 0.0437). 12-month survival for the methotrexate-rituximab cohort was 72.7% (95% CI, 37.1% to 90.3%) versus the alternative treatment cohort 12-month survival of 49.4% (95% CI, 23.7% to 70.8%). 24-month survival for the methotrexate-rituximab cohort was 72.7% (95% CI, 37.1% to 90.3%) versus the alternative treatment cohort 24-month survival of 39.5% (95% CI, 14.9% to 63.6%). Median survival for the alternative treatment cohort was 11 months (95% CI, 2.2 to 28.6), while the median survival for the methotrexate-rituximab regimen was not reached. Stratified by radiation, survival rates were significantly better in the radiation cohort than the cohort without radiation (Log-Rank p-value 0.0040). 12-month survival for the radiation cohort was 90% (95% CI, 47.3% to 98.5%) versus the cohort without radiation 12-month survival of 40.5% (95% CI, 17.7% to 62.3%). 24-month survival for the radiation cohort was 90% (95% CI, 47.3% to 98.5%) versus the cohort without radiation 24-month survival of 33.7% (95% CI, 12.9% to 56.1%). Median follow-up for all patients was 21.5 months (95% CI, 16 to 42.1). Conclusions: The combination of methotrexate at 3.5 g/m2 with rituximab is a valid treatment regimen for primary CNS lymphoma. Patients may be spared toxicity by using a methotrexate dose of 3.5 g/m2 rather than 8 g/m2. The addition of radiation provided a significant survival advantage in this observational study, however, radiation deferred until progression may be a viable alternative.
Phase I study of anti-PlGF monoclonal antibody (mAb) RO5323441 (RO) and anti-VEGF mab bevacizumab (BV) in patients with recurrent glioblastoma (GBM).
Authors: Lassen Ulrik Niels , Chinot Oliver L. , McBain Catherine , Sorensen Morten , Larsen Vibeke Andree , Barrie Maryline , Roth Patrick , Krieter Oliver , Wang Karen , Habben Kai , Tessier Jean , Lahr Angelika , Whiley Matt , Weller Michael
Published: March 2020

2092

Background: BV inhibits VEGF and is approved for progressive GBM following prior therapy. The placental growth factor (PlGF) is a member of the VEGF family and PlGF expression has been shown to correlate with tumor stage and survival in several human malignancies. In cancer patients (pts) PlGF is up-regulated upon treatment with VEGF inhibitors. RO is a humanized IgG1 mAb directed against PlGF that has demonstrated antitumor activity in an orthotopic GBM model. Single agent RO was previously tested in advanced solid tumors. Methods: Eligibility criteria included histologically confirmed GBM with documented radiographic progression upon front line therapy, ≥18 years of age, KPS ≥70, adequate bone marrow reserve and organ function. Prior treatment with VEGF/PLGF targeted therapies was not permitted. Three to six pts were enrolled per dose level (DL), the MTD defined as the dose with DLTs ≤ 1/6 pts during 28-days of cycle 1, using CTCAE v4. Results: A total of 22 pts (16m/6f) have been enrolled in 3 DLs: RO 625mg (4 pts), 1250mg (6), and 2500mg (12) IV every 2 weeks (q2w), each in combination with BV 10mg/kg IV q2w. Median age: 58 years (range 37-72). RO serum concentrations increased proportionally, while serum exposures of BV were similar between all DLs. Two pts experienced a DLT: Meningitis G3 (1250 mg) and cerebral infarction G3 (2500 mg). Most commonly reported adverse events included hypertension (14 pts), headache (11), dysphonia (10), fatigue (6), nasopharyngitis (5), epistaxis (4), constipation (4), nausea (3), and arthralgia (3). Across all DLs tested, the overall response rate by RANO criteria was 22.7%. Conclusions: The tolerability of RO in combination with BV is acceptable; a MTD was not determined. Anti-PlGF treatment does not appear to add on clinical activity observed for single agent BV in recurrent GBM. Clinical trial information: NCT01308684.
Dose-finding and safety study of an oncolytic polio/rhinovirus recombinant against recurrent glioblastoma.
Authors: Desjardins Annick , Sampson John Howard , Peters Katherine B. , Ranjan Tulika , Vlahovic Gordana , Threatt Stevie , Herndon James Emmett , Friedman Allan H. , Friedman Henry S. , Bigner Darell D. , Gromeier Matthias
Published: March 2020

2094

Background: Current therapies for glioblastoma are limited by ineffective delivery beyond the blood-brain barrier, limited diffusion of macromolecules, and lack of tumor specificity. Sustained direct intracerebral infusion at slow flow rates [convection-enhanced delivery (CED)] can overcome delivery barriers. PVSRIPO is the live attenuated, oral (SABIN) serotype 1 poliovirus vaccine containing a heterologous internal ribosomal entry site stemming from human rhinovirus type 2. PVSRIPO recognizes nectin-like molecule-5, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. We report the results of an ongoing phase I study evaluating PVSRIPO when delivered by CED. Methods: Eligible on study are adult patients with: 1-5 cm of measurable supratentorial recurrent glioblastoma ≥1cm away from the ventricles; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; KPS ≥70%; and positive anti-poliovirus titer. PVSRIPO is delivered intratumorally by CED over 6.5 hours. PVSRIPO dose escalation is accomplished by increasing agent concentration, allowing flow-rate and infusion volume to remain constant. Two-step continual reassessment method is used for dose escalation, with one patient each treated on dose levels 1-4, and a possibility of up to 13 patients on dose level 5. Results: Thus far, a total of five patients have been treated on study. No related or unrelated grade 3 or higher adverse events have been observed. Grade 1 adverse events possibly related to the study drug or procedure include one each of fever, cough, nasal congestion, vomiting, headache, hemiparesis, and lethargy. Grade 2 adverse events include one each of diarrhea and seizure. Patient #1 had failed bevacizumab prior to enrollment and remains disease free more than 9 months post PVSRIPO. Two more patients are disease free 8+ and 2+ months post treatment, respectively. One patient had pathology confirmed disease recurrence two months post treatment and one patient came off study due to clinical decline four months post treatment. Conclusions: Infusion of PVSRIPO via CED is safe thus far and encouraging efficacy results are observed. Updated results will be presented. Clinical trial information: NCT 01491893.
Molecular screening for cancer treatment optimization (MOSCATO 01): A prospective molecular triage trial—Interim results.
Authors: Hollebecque Antoine , Massard Christophe , De Baere Thierry , Auger Nathalie , Lacroix Ludovic , Koubi-Pick Valerie , Vielh Philippe , Lazar Vladimir , Bahleda Rastislav , Ngo-camus Maud , Angevin Eric , Varga Andrea , Deschamps Frederic , Gazzah Anas , Mazoyer Clement , Richon Catherine , Vassal Gilles , Eggermont Alexander M. , Andre Fabrice , Soria Jean-Charles
Published: March 2020

2512

Background: Characterization of the genomic alterations (GA) that could drive tumor growth of an individual patient (pt) is now critical to better select targeted therapies in phase I trials. Methods: Pts with advanced solid tumors, who failed at least one line of standard therapy, were offered an on-purpose tumor biopsy for molecular characterization. Biopsies were mainly obtained using 18G needles under CT or ultra-sound control, from metastatic or primary tumor sites. DNA extracted from fresh tumor biopsies was analyzed by CGH (Agilent platform) (if ≥ 50% tumor cells in the sample) and by sequencing for 30 target genes (if ≥ 30% tumor cells in the sample). An expert panel of scientists and clinicians reviewed results to determine the biological signification of the GA and match such pts to the most relevant targeted therapy available (mainly in early clinical trials). PFS using therapy based on GA was compared to the PFS for the most recent therapy on which the pt had just experienced progression (PFS ratio). Results: From December 2011 to august 2012, 129 heavily pretreated pts (median of 3 previous lines) were consented. Among them, 111 (86%) had a dedicated tumor biopsy. An actionable target was identified in 52 patients (40%). Among them, 25 pts (23% of biopsied pts) have been treated with a targeted therapy. The median time between biopsy and molecular results was 21 days [17 – 28]. GA of interest encompassed FGF ligand or receptor amplification (n=9), cyclin amplification or deletion (n=4), KRAS/BRAF/NRAS mutation (n=3), PI3K amplification or PTEN deletion (n=3), EGFR amplification or mutation (n=3) (outside lung cancer), HER2 amplification (n=2) (outside breast cancer), EML4/ALK translocation (n=1). Among the 25 pts treated according to their GA, we observed 5 PR (20%), 14 SD (56%) and 3 PD (12%). Three pts (12%) were not evaluable because of early discontinuation of the therapy. PFS ratio was >1.3 among 9 out of 19 evaluable pt (47%). Conclusions: High throughput molecular analysis is feasible in daily practice. It allows enrichment of phase I trials with specific GA, and leads to promising anti-tumor activity (20% PR as compared to the classical 7-10% PR obtained in all comers phase I trials). Clinical trial information: NCT01566019.
A phase I first-in-human study of REGN910 (SAR307746), a fully human and selective angiopoietin-2 (Ang2) monoclonal antibody (MAb), in patients with advanced solid tumor malignancies.
Authors: Papadopoulos Kyriakos P. , Sahebjam Solmaz , Kelley Robin Katie , Tolcher Anthony W. , Razak Albiruni R.A. , Patnaik Amita , Bedard Philippe L. , Arcos Rebecca , Adriaens Lieve , Brownstein Carrie M. , Lowy Israel , Gao Bo , DiCioccio A Thomas , Trail Pamela , Siu Lillian L.
Published: March 2020

2517

Background: REGN910 is a selective, fully human Ang2 MAb that potently blocks signaling through the Tie2 receptor regulating tumor angiogenesis and growth. In multiple mouse xenograft models of human solid tumors, REGN910 inhibits tumor growth. Methods: This first-in-human phase I study (3+3 design) explored the safety, recommended phase II dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of REGN910 as a single agent. REGN910 was given IV at escalating doses. At RP2D, expansion cohorts were initiated to confirm safety and assess anti-tumor activity in about 20 patients (pts). Results: 37 pts [17M/20F; median age 57 (range 22-82); ECOG PS 0(9)/1(28)] were enrolled. Twenty-three (23) pts were enrolled in the dose escalation cohorts. No DLTs were reported, and a MTD was not reached. Most common G1/2 treatment-related adverse events (TRAEs) were fatigue 7(19%), peripheral edema 6(17%), diarrhea 5(14%), abdominal distension 4(11%), and decreased appetite 4(11%). There were no ≥ Grade 3 TRAEs. A confirmed sustained PR (16 wks) was observed in 1 pt with adrenocortical cancer treated at 1 mg/kg. SD (range 6.9-46.8 wks) was reported for 17 of 32 (53%) pts evaluable for efficacy. Fourteen pts received treatment >16 wks. One pt with thyroid cancer had SD for 46 wks, and 1 pt with hepatocellular cancer had SD for 16 wks with ≥50% decline in alpha-fetoprotein. Across all dose levels, REGN910 pharmacokinetics appeared linear and dose-proportional. The PK profile was characterized by an initial distribution and a single mono-exponential elimination phase. Total circulating serum Ang2 levels appeared saturated following treatment in all cohorts, indicating systemic target engagement at all doses tested. Conclusions: Administration of REGN910 in patients with advanced cancer is well tolerated, with generally mild and moderate TRAEs. Dose escalation is completed, and enrollment to the expansion cohorts continues. The safety profile supports combination with chemotherapy and/or other anti-angiogenic agents. Clinical trial information: NCT01271972.
Phase I, first-in-human, open-label, dose-escalation study of U3-1565, a fully human anti-HB-EGF monoclonal antibody, in patients with advanced solid tumors.
Authors: Moore Kathleen N. , Bendell Johanna C. , Olszanski Anthony J. , Desai Madhuri , Jansen Mendel , Scheyer Richard David , Senaldi Giorgio , LoRusso Patricia
Published: March 2020

2519

Background: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an EGF family member and a ligand for EGFR and Her4. U3-1565 is a fully human anti-HB-EGF monoclonal antibody with preclinical anti-tumor and anti-angiogenesis activity. In this study, we evaluated safety, tolerability, immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of U3-1565 in patients with advanced solid tumors refractory to standard treatment. Methods: The 3+3 method of enrollment and dose-escalation was used to test U3-1565 at 2, 8, 16, and 24 mg/kg once every two weeks (with the second dose given three weeks after the first), and at 24 mg/kg weekly. Results: 15 patients (11 females, 4 males; median age 62 (range 47-77) years; 5 CRC, 5 NSCLC, 3 ovarian and 2 other cancer) were enrolled, 3 in each dose level cohort. No dose-limiting toxicity was observed and a maximum tolerated dose was not reached. The highest administered dose of 24 mg/kg weekly generated Cmin above the predetermined target concentration corresponding to Cave resulting in 90% preclinical tumor growth inhibition. U3-1565 was safe and well tolerated with related AE consisting of infrequent and non-dose-related G2 (fatigue, anemia, and appetite loss, seen in 20, 13, and 7% of cases, respectively) and G1 toxicities. No anti-U3-1565 antibody was detected. U3-1565 showed bi-exponential disposition with Cmax and AUC increasing proportional to the dose across all dosing regimens. 13 patients discontinued the study, 12 due to progressive disease and 1 due to non-drug-related AE. After 6 months on study, 2 patients entered study extension phase: A 77 year-old female with NSCLC given 24 mg/kg every two weeks, showed SD (best SLD change -3%) for 26 weeks before progression; and a 76 year-old female with CRC given 24 mg/kg weekly, showed PR (best SLD change -35%) and remains on treatment after 71 weeks. Conclusions: U3-1565 is safe and well tolerated up to 24 mg/kg weekly. Anti-tumor activity was observed and is being further explored in an open-label, dose-expansion study. Clinical trial information: NCT0129041.
A phase I, dose-escalation trial of continuous and pulsed-dose afatinib (A) combined with pemetrexed (P) in patients (pts) with advanced solid tumors: Final analysis.
Authors: Chu Quincy S. , Sangha Randeep S. , Hotte Sebastien J , Sergenson Gwen , Chand Vikram K. , Sufan Roxana , Gu Yu , Schnell David , Hirte Hal W.
Published: March 2020

2523

Background: A is an irreversible ErbB Family Blocker that has shown additive effects when combined with P in EGFR-mutant NSCLC cell lines. This Ph I trial assessed the MTD, safety and PK of continuous and pulsed-dose A + P in pts with advanced solid tumors. Methods: In a3+3 dose-escalation design, IV P (500 mg/m2) was administered on day (d) 1 of each 21-d cycle combined with either continuous oral A qd (Schedule A; SA) on d1–21 (d2–21 in Cycle 1) or pulsed-dose oral A qd (Schedule B; SB) on d1–6 of each 21-d cycle. In SA, A starting dose was 30 mg, escalated to maximum of 50 mg. Once the MTD was reached in SA, A was administered at a starting dose of 50 mg in SB. Pts received up to 6 cycles of P with the option for A monotherapy thereafter. P and steady state A PK were analyzed by intra-individual comparison in SA only for possible drug–drug interaction. Results: 53 pts were treated (SA: n=23, median age 58 yrs; ECOG 0/1/2 [30%/65%/4%]; SB: n=30, median age 62 yrs, ECOG 0/1/2 [27%/70%/3%]). MTD of A in SA was 30 mg; 8 pts had dose-limiting toxicities (DLTs) in Cycle 1 (40 mg: 2/3 pts; 30 mg; 6/19 pts). 30-mg cohort included 19 evaluable pts; 1 pt was replaced during expansion (incomplete PK collection) and had a DLT. MTD of A in SB was 50 mg; 11 pts had DLTs in Cycle 1 (70 mg: 4/5 pts; 60 mg: 6/17 pts; 50 mg: 1/6 pts). Most frequent drug-related AEs in SA were diarrhea (91%), stomatitis (65%) and rash (61%) and in SB were diarrhea (83%), rash (83%) and fatigue (80%); most were Grade 1/2. 6 pts in SA and 8 pts in SB completed 6 treatment cycles; 1 pt in each schedule remain on treatment. Best response in SA was 1 confirmed partial response (CPR; NSCLC, prior sequential chemotherapies and erlotinib) and 6 pts with stable disease (SD). In SB, best response was 1 CPR (bladder cancer, prior sequential chemotherapies) and 10 pts with SD. No clinically relevant PK interactions between A and P were observed. Conclusions: Continuous or pulsed-dose A combined with P exhibited a manageable safety profile. No clinically relevant PK interactions were seen in SA. Continuous dose A 30 mg/d with P 500 mg/m2 (d1 of each 21d cycle) is the recommended dose for further Ph II studies. No apparent safety or dose advantage was observed in SB. Clinical trial information: NCT01169675.
Phase Ib safety trial of CVX-060, an intravenous humanized monoclonal CovX body inhibiting angiopoietin 2 (Ang-2), with axitinib in patients with previously treated metastatic renal cell cancer (RCC).
Authors: Gollerkeri Ashwin , Gordon Michael S. , Burke John M. , Hauke Ralph , Tomasek Jiri , Richards Donald A. , DiSimone Christopher , Tykodi Scott S. , Mehta Amit R. , Chen Charles , Perea Rachelle , Vogelzang Nicholas J.
Published: March 2020

2533

Background: PF-04856884 is a recombinant humanized monoclonal antibody fused to two Ang-2 binding peptides. Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factors (VEGFs) that is approved for patients (pts) with advanced renal cell cancer who failed 1 prior therapy. Metastatic RCC (mRCC) is an angiogenic tumor sensitive to VEGF tyrosine kinase inhibitors. Resistance to VEGF targeted therapy may be mediated by Ang-2. Methods: In Part I (safety lead in) of the study, the primary endpoint was treatment related dose limiting toxicities (DLT) in pts with mRCC who had received 1-3 prior treatments. Pts received PF-04856884 (15 mg/kg/week) plus axitinib (5 mg BID) for 4 week cycles (the recommended Phase II dose of each) and were assessed for DLT, PK, and potential predictive biomarkers (Ang-2 and VEGF-A). For Part II (Phase II portion), pts with mRCC who had received 1 prior anti-VEGF agent were to be randomized to PF-04856884 + axitinib or axitinib alone to assess median progression free survival. Results: Part I enrolled 18 pts with median age of 62.5 years (39-82), and ECOG performance status of 0-1. One pt had a DLT of Grade 4 pulmonary embolism (PE). Most common related AEs: anorexia in 10 pts (56%), diarrhea 8 (44%), fatigue 8 (44%), nausea 7 (39%), hypertension 6 (33%) and vomiting 6 (33%). Treatment-related thromboembolic events (TEEs) were observed: PE in 2 pts (11%), and cerebrovascular accident (CVA), presumed bowel ischemia, and possible cardiac chest pain in 1 pt (6%) each. One pt had Grade 2 venous thrombosis unrelated to either treatment. Due to the reported TEE, PF-04856884 was reduced to 10 mg/kg in pts remaining on study and enrollment to Part II was not initiated. No significant PK interaction was observed. Two pts had partial response (PR) and 1 pt had unconfirmed PR. Twelve pts (66%) remained on study ≥91 days with a median duration of 120 days (8-279). Anti-PF-04856884 antibody results are not available. Conclusions: Due to the higher than expected TEEs, alternate doses of PF-04856884 and/or disease settings are being considered. Clinical trial information: NCT01441414.
Characteristics and survival of patients with advanced cancer and TP53 mutations in phase I clinical trials.
Authors: Said Rabih , Ye Yang , Hong David S. , Janku Filip , Fu Siqing , Naing Aung , Wheler Jennifer J. , Kurzrock Razelle , Thomas Christoforos , Palmer Gary A. , Hess Kenneth R. , Wolff Robert A. , Tsimberidou Apostolia Maria
Published: March 2020

2545

Background: The classical hot spot mutations within the central sequence-specific DNA-binding region of p53 protein (R175H in exon 5 and G245S, R248Q, R249S, R273H and R282W in exon 8) disrupt its ability to bind to DNA. These inactivating point mutations of p53 may result in loss of its function and/or acquisition of a gain of function, which has been associated with the development of invasive and metastatic tumors in mouse models. We assessed the frequency and survival of p53 mutations in patients with advanced cancer. Methods: P53 mutation in patients’ tumor was identified in a CLIA-certified laboratory using PCR, sequenom analysis or next generation sequencing. Results: P53 mutations were identified in 212 patients. Median survival by tumor type and distribution of p53 mutations by exon are shown in the Table. The median survival (from time of referral to Phase I clinic) by mutations in “hot spot” amino acids was as follows: R175H, 9.1 months (n=18); R248Q, not reached/5 deaths (n=22); R273H, 12.6 months (n=11); other mutations, 11.9 months (n=160). The median survival of patients with a tumor mutation in exons 5 or 8 appeared to be shorter than that of patients with mutations in other exons (9.4 vs. 14.6 months) although the difference was not statistically significant (p=.12) owing to the small number of patients. Conclusions: Our results demonstrate that the distribution and clinical significance of various p53 mutations differs by tumor type and suggest that mutations in R248Q may be associated with longer survival. [Table: see text]
MLN2480, an investigational oral pan-RAF kinase inhibitor, in patients (pts) with relapsed or refractory solid tumors: Phase I study.
Authors: Rasco Drew Warren , Olszanski Anthony J. , Patnaik Amita , Espino Guillermo , Neuwirth Rachel , Faucette Stephanie , Bargfrede Michael , Gangolli Esha A. , Walker Russell M , Kneissl Michelle , Bozon Viviana
Published: March 2020

2547

Background: MLN2480 is an investigational pan-RAF kinase inhibitor. In vivo, MLN2480 showed antitumor activity in melanoma, colon, lung, and pancreatic cancer xenograft models. This first-in-human study aimed to evaluate the safety of MLN2480, determine the MTD/recommended phase 2 dose (RP2D), and evaluate pharmacokinetics (PK) and preliminary efficacy. Methods: Pts aged ≥18 yrs with advanced solid tumors who had failed/were not candidates for standard therapy received oral MLN2480 every other day (Q2D) in 22-d cycles, with dose escalation (3+3 design) based on DLTs in cycle 1. AEs were graded per NCI-CTCAE v4.03. Blood samples for plasma PK assessment were taken pre-dose and at multiple times post-dose, d 1 and 21, cycle 1. Results: 24 pts (10 male, median age 64.5 yrs [range 37–83]) have been treated at 20, 40, 80, 135, 200, and 280 mg (n=4, 3, 3, 3, 4, and 7), respectively. The most common tumors included colorectal cancer in 11 pts and non-small-cell lung cancer in 2 pts. Pts received a median of 2 (range 1–6) cycles. 2 pts treated at 280 mg had DLTs: grade 3 macular rash and grade 3 periorbital edema. 20 pts had drug-related AEs, including fatigue 46%, arthralgia 25%, maculopapular rash 21%, and myalgia 17%. 4 pts had drug-related grade ≥3 AEs, which included the 2 DLTs listed above, anemia, dyspnea, and fatigue. No keratocanthomas/ squamous cutaneous carcinomas have been seen to date. 4 pts discontinued due to AEs. There were 3 on-study deaths (1 treatment-related per investigator; dyspnea and respiratory failure). At 20–200 mg MLN2480 PK data (13 pts) exhibited rapid absorption (median Tmax 2 hr), low fluctuation at steady state (mean peak to trough ratio 2.1), and mean accumulation half-life of 67 hr. Overall mean accumulation was 2.6-fold following repeated Q2D dosing for 21 d. Steady-state (d 21) exposures increased in an approximately dose-proportional manner over 20–200 mg range. No pts had an objective response to date; no pts with BRAF mutation enrolled to date. Conclusions: In this first-in-human study (n=24), the safety profile of MLN2480 up to 200 mg Q2D was acceptable. Accrual continues at 200 mg to confirm the MTD. Melanoma expansion cohorts are planned at the RP2D using a Q2D 28-d cycle. Clinical trial information: NCT01425008.
Heat shock protein 90 (HSP90) inhibition in squamous cell carcinoma of the head and neck (SCCHN): An in vitro analysis with a focus on p16 status.
Authors: Patel Kirtesh R , Wen Jing , Muller Susan , Gao Jingjing , Diaz Roberto , Saba Nabil F. ,   Winship Cancer Institute, Emory University
Published: March 2020

2552

Background: Despite advances in therapy, the overall 5 year survival for SCCHN is close to 50%. Cisplatin and radiation therapy remain the current standard for treating locally advanced SCCHN. Novel treatment approaches are urgently needed, especially in HPV negative disease. We examined the expression of HSP90 in HPV positive and negative SCCHN and investigated if the HSP90 inhibitor ganetespib can sensitize mutant p53 SCCHN to cisplatin and radiation therapy in vitro. Methods: Phase 1 trials of ganetespib at 150 mg/m2 have shown the maximum clinically achievable concentration (CAC) in patients to be ~166 nM. We treated p53 deficient or mutant p53 SCCHN cells (SCC25 and Detroit 568, CAL27and FADU, respectively) with ganetespib at 10-50 nM alone and in combination with cisplatin or radiation therapy and assessed survival. We measured HSP90, HSP70 and p53 protein expression levels in SCCHN cell lines by immunoblotting and analyzed HSP90 protein levels in p16 positive and p16 negative SCCHN tumor samples by immunohistochemistry. Results: Ganetespib at CAC was significantly more cytotoxic in mutant p53 compared to p53 deficient SCCHN cells (p < 0.05). When combined with CAC doses of cisplatin or radiation therapy, ganetespib displayed strong sensitizing activity (p < 0.05 and p < 0.01 respectively). Ganetespib treatment upregulated HSP70 and HSP90 expression while decreasing p53 expression in the mutant cell lines. HSP90 expression was significantly higher in p16 negative than p16 positive SCCHN tumor samples (79.5% vs. 51%, ANOVA p = 0.016). Conclusions: Our results demonstrate a potential efficacy of ganetespib as a single agent and in combination with cisplatin and radiation therapy in SCCHN. HSP90 expression is upregulated in p16 negative SCCHN. Further exploration of the role of HSP90 in SCCHN, and utility of HSP90 inhibitors, is warranted.
A drug-drug interaction study between the strong CYP3A4 inhibitor ketoconazole (keto) and ixazomib citrate (MLN9708), an investigational, orally active proteasome inhibitor, in patients with advanced solid tumors or lymphoma.
Authors: Gupta Neeraj , Venkatakrishnan Karthik , Noe Dennis A , Hanley Michael J , Yu Jiang , Bessudo Alberto , Sharma Sunil , Strother Robert Matthew , Shou Yaping , Nemunaitis John J.
Published: March 2020

2555

Background: MLN9708 is an oral proteasome inhibitor currently being investigated in multiple myeloma and amyloidosis in phase 3 studies. MLN9708 immediately hydrolyzes to its biologically active form, MLN2238, in aqueous solutions or plasma. Metabolism by multiple cytochrome p450s (CYPs) including 3A4 and 1A2 (>25% contribution by each) was expected to be the primary clearance mechanism for MLN2238 based on human liver microsomal metabolism studies. This open-label, multicenter study (NCT01454076) characterizes the effect of CYP3A4 inhibition with keto on single-dose pharmacokinetics (PK) of MLN9708 in a fixed sequence design. Methods: Patients received MLN9708 2.5 mg on d 1 and 15, and keto 400 mg (PO) daily on d 12–25. On d 15, MLN9708 and keto were administered concomitantly. Serial blood samples were collected over 0–264 hr after MLN9708 doses on d 1 and 15 for PK characterization. Plasma PK parameters were estimated by non-compartmental methods. The effect of keto co-administration on MLN9708 AUC0–264hr and Cmaxwas evaluated by Analysis of Variance of log-transformed values. Results: 16 PK-evaluable patients (11 Caucasian, 3 African American, 2 Hispanic; 6M, 10F) with mean (range) age of 61 years (48–79) and body surface area of 1.8 m2 (1.5–2.3) were enrolled. Co-administration of MLN9708 and keto resulted in a 2-fold increase in MLN9708 AUC0–264hr but no change in Cmax(Table). No differences in adverse events were observed +/- the addition of keto, to a single dose of 2.5 mg MLN9708. Conclusions: The observed 2-fold increase in MLN9708 AUC0–264hrwith a strong CYP3A4 inhibitor suggests the contribution of CYP3A4 clearance to the total clearance of MLN9708 is significant. These results support the continued exclusion of strong CYP3A4 inhibitors in ongoing and planned clinical trials of MLN9708. Clinical trial information: NCT01454076. [Table: see text]
Phase I clinical trial of the intraperitoneal (IP) administration of a novel nanoparticle formulation of paclitaxel (NTX).
Authors: Williamson Stephen K. , Wick Jo , Chapman Julia A. , Johnson Gary , Reed Greg , Schulz Thomas K. , Smith Holly , Weir Scott , Decedue Charles J , Howell Jahna , Roby Katherine
Published: March 2020

2558

Background: IP therapy is an attractive option for patients with IP carcinomatosis as many of these malignancies remain confined IP. Agents whose plasma clearance rates substantially exceed their rates of uptake from the peritoneal cavity are especially suited for IP administration. Pre-clinical studies of a novel formulation of nanoparticulate paclitaxel in animal tumor models demonstrated superior activity and substantially reduced systemic toxicity. This allowed for significant IP doses and concentrations, yet yielded very low systemic concentrations of paclitaxel. We report here the results of a Phase I trial of IP administered NTX. Methods: Patients (ECOG≤2) had relapsed, treatment refractory solid IP tumors and adequate organ function. NTX was administered IP as a bolus injection after 500 ml saline followed by IP administration of up to 2 L of saline. We utilized an accelerated dose escalation scheme until one DLT occurred during cycle 1, followed by a standard dose escalation (3+3 design) based on CTCAE V3 toxicities. The pharmacokinetics of IP administered NTX were characterized in plasma and ascites fluid. Secondary objectives were to define the recommended phase 2 dose of NTX, and characterize preliminary activity and toxicity. Results: 20 patients were treated at dose levels from 50 – 275 mg/M2 q 28 days. Primary malignancy was ovarian cancer (74%). Treatment was well tolerated at all dose levels. Common toxicities potentially related to NTX were: gastrointestinal (68%), constitutional (42%), and pain (42%). Average number of cycles received was 2 (range 1 to 6). Best response was stable disease (4 patients, 21%). Median length of disease stability was 99 days (range 85 to 151 days); median time on study patients with stable disease was 313 days (range 142 to 740 days). All Cmax in plasma were less than 35 ng/mL, with ascites fluid Cmax generally greater than 1000 ng/mL. Conclusions: IP NTX is well tolerated. MTD has not yet been reached. Pharmacokinetic data demonstrate significant, persistent IP exposure to paclitaxel with minimal systemic exposure. Accrual at the 275 mg/M2 dose level continues; updated results will be presented. Further clinical development of NTX is indicated. Clinical trial information: NCT00666991.
A phase I trial of GBS-01 for advanced pancreatic cancer refractory to gemcitabine.
Authors: Ikeda Masafumi , Sato Akihiro , Mochizuki Nobuo , Toyosaki Kayo , Miyoshi Chika , Fujioka Rumi , Mitsunaga Shuichi , Shimizu Satoshi , Ohno Izumi , Takahashi Hideaki , Okuyama Hiroyuki , Hasegawa Hiromi , Nomura Shogo , Ohkubo Toshiki , Yomoda Satoshi , Kishino Satoshi , Esumi Hiroyasu
Published: March 2020

2559

Background: Arctigenin, which is abundant in the seeds of Arctium lappa Linné, was found by a novel strategy to attenuate cancer cells’ tolerance to glucose deprivation (antiausterity) and showed antitumor activity in mouse xenograft models. GBS-01 is an orally administered drug and contains rich arctigenin extracted from Arctium lappa Linné, which is one of the traditional herbal medicine. This study investigated the maximum-tolerated dose of GBS-01 based on the frequency of dose-limiting toxicities (DLT) in patients with refractory advanced pancreatic cancer, which is considered as one of the hypoxic cancer. Methods: Histologically or cytologically proven advanced pancreatic adenocarcinoma patients refractory to gemcitabine were enrolled. GBS-01 was administered orally at escalating doses from 3g to 12g qd. DLT was defined as grade 4 hematological toxicities and grade 3 or 4 non-hematological toxicities during first 28 days of the treatment. Response evaluation based on RECIST criteria and progression-free survival were set as secondary endpoint for efficacy evaluation. Results: Fifteen patients (GBS-01 3g: 3 patients, 7.5g: 3 patients, 12g: 9 patients) were enrolled in this trial. All patients were refractory to S-1 as well as gemcitabine. All patients at the three dose levels did not demonstrate any sign of DLT. The main adverse events of this agent were increased γGTP, hyperglycemia, and increased total bilirubin, but all toxicities were extremely mild. Of all 15 enrolled patients, 1 patient showed a partial response and 4 patients had a stable disease. The median progression-free and overall survival time for all patients were 1.05 months and 5.68 months, respectively. Conclusions: The recommended dose of GBS-01 was 12 g qd (4 g as a extract of Arctium lappa Linné), and favorable clinical responses were obtained. A multicenter phase II trial is being planned to evaluate the efficacy and safety of this agent. Clinical trial information: 000005787.
Phase I study of cabazitaxel (Cbz) plus cisplatin (Cis) in patients (pts) with advanced solid tumors: Substudy to evaluate the impact of a strong CYP3A inhibitor (ketoconazole; K) or inducer (rifampicin; R) on the pharmacokinetics (PK) of Cbz.
Authors: Mita Alain C. , Lockhart Albert C. , Wade James Lloyd , Morris John Charles , Rixe Olivier , Dedieu Jean-François , Wack Claudine , Kassalow Laurent , Sarantopoulos John
Published: March 2020

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Background: Cbz is approved for treatment of pts with hormone-refractory metastatic prostate cancer after progression on a docetaxel-containing regimen. The dose-escalation part of this Phase I study (NCT00925743) found the maximum tolerated dose (MTD) of Cbz/Cis to be 15/75 mg/m2. No Cbz–Cis PK interactions were seen. As Cbz is mainly metabolized by CYP3A, the study also evaluated the impact of a strong CYP3A inhibitor (K; study part 3) or strong CYP3A inducer (R; study part 4) on the PK of Cbz in combination with Cis. Methods: The study included pts with metastatic or unresectable solid tumors for which Cis-based therapy was considered appropriate. Pts received Cbz/Cis every 3 weeks at MTD, with K 400 mg (part 3) or R 600 mg (part 4) administered orally once daily prior to, on, and after Cycle 2 Day 1 for a total of 10 (K) or 14 (R) days. In part 3, the Cbz/Cis dose was 5/75 mg/m2 in Cycles 1 and 2 to provide a safety margin to the MTD. Effects on Cbz PK were assessed with a linear mixed-effects model. The primary endpoint was Cbz clearance (CL). Safety assessments included adverse events (AEs) and laboratory abnormalities. Results: The PK population included 23 pts (part 3) and 21 pts (part 4). Repeated administration of K resulted in a 20% decrease in Cbz CL (L/h/m2) (geometric mean ratio [GMR]: 0.80; 90% confidence interval [CI]: 0.55, 1.15; n = 18), corresponding to a 25% increase in AUC (ng*h/mL/mg/m2) (GMR: 1.25; 90% CI: 0.86, 1.81; n = 18). Repeated administration of R resulted in a 21% increase in Cbz CL (L/h/m2) (GMR: 1.21; 90% CI: 0.95, 1.53; n = 20), corresponding to a 17% decrease in AUC (ng*h/mL/mg/m2) (GMR: 0.83; 90% CI: 0.65, 1.05; n = 20). The GMR of AUC0–24was 1.09 (90% CI: 0.9, 1.33; n = 21), suggesting a low impact of R during the initial phases of Cbz elimination. The most frequent AEs included nausea (part 3: 68%; part 4: 74%), vomiting (part 3: 68%; part 4: 74%) and fatigue (part 3: 52%; part 4: 70%). Conclusions: The CL of Cbz was decreased by 20% by co-administration with K and increased by 21% by co-administration with R. Safety results were consistent with prior findings for this Cbz/Cis combination. Clinical trial information: NCT00925743.
Phase I dose-escalation, open-label study of HSP990 administered orally in adult patients with advanced solid malignancies.
Authors: De Mattos-Arruda Leticia , Siu Lillian L. , Cortes Javier , Berge Yann , Razak Albiruni R A , Rodon Ahnert Jordi , Cottura Ewa , Bedard Philippe , Akimov Mikhail , Lu Hong , Pain Scott , Kaag Audrey , Delord Jean-Pierre
Published: March 2020

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Background: NVP-HSP990 is a synthetic small molecule that potently and selectively inhibits heat-shock protein 90. HSP990 leads to degradation of client proteins, offering potential simultaneous blockade of multiple oncogenic signaling pathways. The primary objective of this Phase l first-in-man study (NCT00879905) was to determine the single-agent MTD of HSP990 administered once (qw) or twice (biw) weekly to patients (pts) with advanced solid malignancies (preselected CYP2C9 genotypes only). Secondary objectives included safety, efficacy, PK, and biomarkers. Methods: HSP990 was administered orally qw or biw in 28-day cycles. Dose escalation was guided by a Bayesian logistic regression model. The MTD was determined by assessing DLTs in Cycle 1. Eligible pts included those with histologically confirmed advanced solid tumors that had progressed on standard therapy or for whom no standard therapy exists. Results: 64 pts (median age 57 yr: 44% male; 37.5% Stage IV; WHO PS 0/1) received HSP990. 53 pts received HSP990 qw at 2.5, 5, 10, 20, 30, 50 or 60 mg; and 11 pts received HSP990 biw at 25 mg. Median duration of exposure was 8 wks; 12 pts remained on treatment for >16 wks. DLTs occurred in 7 pts: 4/22 at 50 mg qw (including G3 diarrhea, G3 QTc prolongation, G4 ALT/AST elevations); 2/5 at 60 mg qw (including G3 tremors); and 1/11 at 25 mg biw (including G2 ataxia, G2 confusion, G2 visual hallucination). The 50-mg qw dose was declared as the MTD. Further dose escalation was not possible due to neurologic toxicity. Most common reported CTCAE G3/4 AEs were diarrhea (12.5%), increased ALT/AST (11% each), anemia, or cholestasis (6% each). HSP990 had Tmax of 3 h and T½ of ~20 h. Large inter-patient variability in PK exposures was observed. For qw dosing, approximate dose-dependent HSP70 induction was observed from 5−30 mg qw, which plateaued after 20 mg qw. There were no objective responses; however, 25 pts (39%) had SD. (RECIST v1.0). No pt showed a complete metabolic response (MR; by FDG-PET) and 11 pts (17%) showed a partial MR. All pts discontinued treatment, primarily due to disease progression (84%). Conclusions: The single-agent MTD of HSP990 in pts with advanced solid tumors was 50 mg qw. SD was observed in 39% of pts. Clinical trial information: NCT00879905.
Use of gene expression profiling to identify responsive patients treated with carboplatin (Carb), paclitaxel (Pac), and everolimus as first-line treatment for cancer of unknown primary (CUP): NCCTG N0871 (Alliance).
Authors: Goetz Matthew P. , Foster Nathan R. , Meyers Jeffery P. , Steen Preston D. , Visscher Daniel W. , Yoon Harry H. , Pillai Raji , Prow Debra M. , Reynolds Christopher M. , Marchello Benjamin T. , Mowat Rex B. , Mattar Bassam Ibrahim , Erlichman Charles ,   Alliance for Clinical Trials in Oncology
Published: March 2020

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Background: Empiric chemotherapy (taxane/platinum) is standard for CUP. Because prognosis is poor, novel approaches are needed. The PI3K/mTOR pathway is frequently dysregulated in cancer. Everolimus (E), an mTOR inhibitor, is approved for multiple malignancies. We performed a phase II study of Pac + Carb + E as first-line therapy in metastatic CUP patients (pts). We additionally determined if a gene expression profiling (GEP) test that identifies tissue of origin (Pathwork Tissue of Origin) could identify responsive pts. (NCT00936702) Methods: Newly diagnosed, untreated CUP pts were eligible. Central pathology review confirmed CUP prior to registration; GEP was performed on formalin fixed tumor tissue. Pac (200 mg/m2), Carb (AUC=6) and E (30 mg once weekly) were delivered every 3 wks until progression or intolerable adverse events (AEs). The primary endpoint was confirmed response, with ≥11 of 50 responses (22%) needed for trial success. Secondary endpoints were OS, progression-free survival (PFS) and AEs. Results: 46 pts (median age 61) received a median 4 cycles (range: 1-33). 39 (85%), 21 (46%) and 1 (2%) experienced ≥1 grade (gr) 3+, 4+, or 5 (sepsis) AE, with gr 3+ hematologic AE most common (74%). Of 44 evaluable pts, 15 had a confirmed response (RR 34%, 95% CI: 21-50%), with a median PFS and OS of 4.1 and 10.1 mos, respectively. Adequate tissue for GEP was available in 36 pts and predicted 10 different sites of origin. In pts with a predicted tissue of origin in which taxane/platinum is standardly used, higher RR and significantly longer PFS and OS were observed compared with pts whose GEP identified a malignancy where taxane/platinum is not standard (Table). Conclusions: In pts with untreated CUP, Carb +Pac +E demonstrated promising antitumor activity. The GEP test identified patients clinically responsive to Carb/Pac/E therapy, and may be useful to select CUP pts for specific antitumor regimens. Clinical trial information: NCT00936702. [Table: see text]
Phase I study to evaluate the safety and to assess the food effect of HM781-36B, a novel pan-HER inhibitor continuously given in patients with advanced solid tumors.
Authors: Kim YuJung , Oh Jisu , Kim Tae Min , Han Sae-Won , Lee Keun Wook , Kim Jee Hyun , Im Seock-Ah , Bae Kyun-Seop , Noh Yook-Hwan , Nam Hyun-Jin , Park Kyung-Mi , Son Jeewoong , Bang Yung-Jue
Published: March 2020

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Background: HM781-36B, a novel pan-HER tyrosine kinase inhibitor, showed potent in vitro and in vivo antitumor activities for EGFR mutant models including T790M mutation. In the previous 2-weeks on, 1-week off phase I study, the maximum tolerated dose (MTD) was determined as 24 mg/day. Phase I study with a continuous daily dosing schedule was conducted to determine the recommended dose (RD), and to assess the effect of food on pharmacokinetics (PK) in patients (pts) with advanced solid tumors. Methods: Eligible pts had advanced malignancies refractory to standard therapies. Standard 3+3 scheme was used in the dose escalation study, and additional 8 patients were enrolled to test food effects. Results: 20 pts (median age: 55 years [range32-77], M:F=13:7, ECOG PS 0/1/2/3 8/12/0/0) were enrolled (5 NSCLC, 4 colon cancer, 3 stomach cancer, 2 breast cancer, 2 rectal cancer, 2 common bile duct cancer, 1 pancreatic cancer and 1 esophageal cancer); 12 in the dose escalation and 8 in the food effect study cohort. Twelve pts were heavily pretreated(≥4 regimens). Dose limiting toxicities (DLTs) were G3 anorexia in 1 pt at 18mg/day, G3 diarrhea and anorexia in 1 pt, and drug compliance <80% due to G2 adverse events in 1 pt at 24mg/day. The MTD was determined as 18 mg/day, and RD was determined as 16 mg/day. The most common drug-related adverse events were diarrhea, stomatitis, skin rash, paronychia, pruritus and anorexia. Among 16 evaluable pts, 4 achieved partial responses (PR)[1 NSCLC, 2 breast cancer, 1 common bile duct cancer], and the duration of response were 32, 40+, 21, and 8 weeks, respectively. Five pts had stable disease (SD). The median duration of treatment in pts with PR or SD was 33.5 weeks (range, 15-82). Under both fasted and fed condition, there were no significant differences of AUClast values, whereas Cmax values were lower in fed condition than in fasted condition. Conclusions: Continuous daily dosing schedule of HM781-36B is safe and well tolerated in advanced solid tumors. It exerts anticancer activity, without being influenced by food. Updated data will be presented at the meeting. Clinical trial information: NCT01455584.
Phase I dose-escalation clinical trial with 5-imino-13-deoxydoxorubicin in cancer patients.
Authors: Hohl Raymond J. , Vestal Robert E. , Holstein Sarah Abigail , Olson Richard D. , Parrott Karen , Walsh Gerald M.
Published: March 2020

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Background: 5-imino-13-deoxydoxorubicin (DIDOX; GPX-150) is a doxorubicin (dox) analog modified in two locations to prevent formation of a) cardiotoxic metabolites and b) reactive oxygen species. In a rabbit model comparing the cardiotoxicity of dox vs. DIDOX, chronic doses of each caused similar myelosuppression, but only dox caused cardiotoxicity as assessed by echocardiography and histopathology scoring. In view of the non-cardiotoxic nature of DIDOX along with its anticancer efficacy in preclinical studies, DIDOX was entered into a Phase I, open-label, non-randomized dose-finding study in up to 30 patients with solid tumors. Methods: Inclusion criteria included progressing solid tumors and cardiac ejection fraction (CEF) 110% of lower limit of institutional normal (assessed by MUGA). There are 8 dose cohorts and up to 8 cycles/cohort, dosing (iv) once every 3 weeks with an accelerated titration dosing design at the three lowest cohorts. Cohort A =14, B=28, C=56, D=84, E=112, F=150, G=200, and H=265 mg/m2/cycle. Dose was escalated to next dose level if < 1 dose limiting toxicity (DLT) is reported. Maximum tolerated dose (MTD) will be exceeded when 2 or more patients in a cohort elicit DLT; the next lower dose is defined as the MTD. DLT occurs when a decrease in CEF is grade 2 or higher, or grade 4 neutropenia lasts > 5 days. Results: Cohorts A-G have been completed. Number of patients for the cohorts are: A=1, B=1, C=1, D=4 E=3 F=3 G=4, and H = 2 (with 4 more to be enrolled in H). No decrease in CEF occurred in any cohorts. There were no DLTs in cohorts A-G. One patient in H had neutropenia grade 4 for 11 days (a DLT). Another patient in H had neutropenia grade 4 for 4 days. There was no disease progression at the completion of dosing for 6 of the 12 patients in cohorts E-H. In contrast, all 7 patients had disease progression in cohorts A-D. Conclusions: No cardiotoxicity was observed in any patient. No DLT was observed in cohorts A-G. With one DLT in cohort H, one more DLT will define MTD for DIDOX at 200 mg/m2. At higher DIDOX doses (E-H), 6 of 12 patients showed no disease progression. (IND No. 77,051). Clinical trial information: NCT00710125.