bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I dose escalation trial of tremelimumab (CP-675,206) administered in combination with PF-3512676 in patients with melanoma or other advanced cancers
Authors: Underhill C. , Millward M. , Lobb S. , McBurnie J. , Meech S. , Gomez-Navarro J. , Readett D. , Bulanhagui C. A.
Published: August 2020

3046

Background: Tremelimumab, a fully human monoclonal antibody specific for cytotoxic T-lymphocyte antigen 4 (CTLA4), and PF-3512676, an oligodeoxynucleotide toll-like receptor 9 agonist, are both novel, targeted immune modulators that can elicit durable antitumor responses in patients with advanced cancer. The tolerability of the combination of these two agents was investigated. Methods: Eligibility criteria included advanced melanoma or other advanced cancer, ECOG performance status of 0 or 1, and no history of autoimmune disease. Patients received intravenous tremelimumab (6.0, 10.0, or 15.0 mg/kg) every 12 weeks plus 0.05 mg/kg subcutaneous PF-3512676 weekly. Further escalation of PF-3512676 (to 0.1 mg/kg and 0.2 mg/kg) was planned once the MTD of tremelimumab had been determined. Primary endpoint was safety of the treatment combination; secondary endpoints included clinical activity, pharmacokinetics (PK), and immunologic measurements. Results: To date, 15 patients (melanoma, n = 12; mesothelioma, n = 2; prostate, n = 1) have been treated in this study: 3 at dose level 1 (6 mg/kg tremelimumab + 0.05 mg/kg PF-3512676); 6 at dose level 2 (10 mg/kg tremelimumab + 0.05 mg/kg PF-351276); and 6 at dose level 3 (15 mg/kg tremelimumab + 0.05 mg/kg PF-3512676). There were two DLTs at dose level 3: G3 diarrhea (n=1) and G3 nausea and vomiting associated with biopsy-proven duodenitis (n=1). One DLT, G3 hypophysitis, occurred at dose level 2. Patients with DLTs responded to corticosteroid therapy. Common adverse events included mild to moderate PF-3512676 injection site reactions (n=14), mild to moderate flu-like symptoms (n=9), G1/2 diarrhea (n=9), and G1/2 nausea (n=8). Presently, there are 2 PRs (13%) and 5 SDs among the 15 patients. Updated safety, efficacy, and PK data will be reported. Conclusions: At dose levels tested to date, the combination of tremelimumab and PF-3512676 has been tolerable and showed evidence of antitumor activity in patients with advanced melanoma. The MTD for this combination has yet to be determined, and a fourth intermediate dose level (10 mg/kg tremelimumab + 0.1 mg/kg PF-3512676) is currently being explored.

[Table: see text]
Characterization of an antitumor immune response after light-activated drug therapy using talaporfin sodium in a spontaneously metastasizing mammary tumor model
Authors: Bromley E. , Owczarczak B. , Keltner L. , Wang S. , Gollnick S. O.
Published: August 2020

3052

Background: An innovative light-activated drug therapy (Litx) is a cytoreductive treatment that uses light-emitting diodes to activate talaporfin sodium (LS11), a water-soluble drug, resulting in the production of singlet oxygen. Tumor destruction involves direct and indirect tumor kill through apoptosis, vascular occlusion, and potentially antitumor immunologic effects. To provide evidence for the potential antitumor immunologic effects, we have used the therapy to treat primary tumors and examine prevention of metastases in the 4T1 tumor model, an aggressive, spontaneously metastasizing murine mammary tumor model that mirrors human breast cancer. When grown in the mammary fat pad of BALB/c mice, untreated 4T1 tumors rapidly metastasize to lung, liver, lymph nodes, and brain. Methods: To confirm tumor kill by this therapy, the primary 4T1 tumors grown in mice were treated and animal survival was followed. To determine whether the therapy could enhance antitumor immunity and reduce metastases, the lymph node (LN) cells from treated and control mice were transferred to naïve recipient mice. Recipients were challenged with a tumorigenic dose of 4T1 cells 3 days after adoptive transfer and primary and secondary tumor growth in the recipients was examined. Results: Treatment of primary tumors significantly increased survival (p≤0.01) when compared to animals treated with either light or drug alone. LN cells isolated from treated mice, but not control mice, significantly inhibited primary tumor growth in recipients (p≤0.0001) and dramatically reduced the number of lung metastases present 40d after tumor challenge (p≤0.02). The ability to inhibit primary and secondary tumor growth in recipients depended on the presence of CD8+ T cells; depletion of CD8+ T cells from the LN abolished the effect. Preliminary evidence for such effect on untreated tumors has been observed in human trials of this therapy. Conclusions: These results indicated that this light-activated drug therapy not only destroyed the treated tumors directly but also controlled growth of untreated tumors through induction of a specific host antitumor immune response mediated by CD8+ T cells.

[Table: see text]
A phase I study of a DNA plasmid based vaccine encoding the HER2/neu (HER2) intracellular domain (ICD) in subjects with HER2+ breast cancer
Authors: Salazar L. G. , Slota M. , Wallace D. , Higgins D. , Coveler A. L. , Dang Y. , Childs J. , Bates N. , Waisman J. , Disis M. L.
Published: August 2020

3054

Background: HER2 is overexpressed in 25% of breast cancers and plays a role in the malignant transformation of cells. Vaccine-induced immunity against the HER2 ICD correlates with antitumor responses in animal models. DNA-based vaccines offer a strategy to immunize against multiple tumor antigens and are able to elicit both CTL and T helper immune responses. Plasmid DNA can also remain at the vaccine site, providing a constant source of antigen. However, DNA vaccines have been poorly immunogenic due in part to inefficient APC transfection. Intradermal (i.d.) delivery of DNA vaccines with GM-CSF as adjuvant may enhance immunogenicity due to local influx of dermal Langerhans cells. A phase I study was conducted to evaluate the safety and immunogenicity of a DNA-based vaccine encoding the HER2 ICD. Methods: 44 subjects with stage III and IV HER2+ breast cancer in complete remission were enrolled sequentially into 2 vaccine arms (22 subjects/arm) and received 10μg pNGVL3-hICD (Arm 1) or 100μg pNGVL3-hICD (Arm 2). All vaccines were admixed with 100μg GM-CSF and given i.d. monthly for a total of 3 vaccines. Toxicity was assessed at baseline, during vaccination, and at follow-up. Immune responses were assessed with IFN-γ ELISPOT at baseline and post-vaccination. Vaccine site biopsies were analyzed for plasmid persistence via RT-PCR, 1 and 6 months after vaccination. Results: 43 subjects (21 in Arm 1; 22 in Arm 2) completed 3 vaccines. Vaccine-related toxicity in both arms was primarily grade I/II; no cardiac or grade IV toxicity was observed. 13/21 (62%) subjects in Arm 1 developed T-cell immunity, defined as HER2-specific T cell precursors:PBMC, to the HER2 protein (median 1:5,972, range 1:717–1:3,000,000) and to p776, a HER2 pan DR binding epitope (median 1:3,150, range 1:543–1:108,696). 13/19 (68%) subjects in Arm 1 had persistent plasmid DNA at the vaccine site. ELISPOT and RT-PCR analysis for Arm 2 are on-going. Conclusions: Immunization with a DNA plasmid-based HER2 vaccine is safe and immunogenic. Moreover, plasmid DNA persists at the vaccine site post-immunization and HER2+ cancer patients are able to develop immunity to the HER2 ICD.

No significant financial relationships to disclose.
HER2/neu (HER2) specific T-cell immunity in patients with HER2+ inflammatory breast cancer (IBC) and prognosis
Authors: Salazar L. G. , Wallace D. , Mukherjee P. , Higgins D. , Childs J. , Bates N. , Coveler A. L. , Disis M. L.
Published: August 2020

3057

Background: IBC is rare, highly aggressive, and associated with worse prognosis when compared to non-IBC tumors. Moreover, multimodality treatment has had little impact on overall prognosis. HER2 is overexpressed in about 40% of IBC tumors and is associated with worse overall survival (OS). We have developed vaccines that elicit both HER2-specific CD4+ and CD8+ T-cell immunity in HER2+ cancer patients. Generation of HER2-specific T-cell immunity could (1) target immunogenic and biologically relevant proteins such as HER2 in IBC, (2) result in immunogenic eradication of HER2+ tumor cells, and (3) potentially prevent disease relapse when used in the adjuvant setting after standard therapy. A retrospective analysis of IBC patients immunized with HER2 vaccines was conducted to better understand the development of HER2-specific T-cell immunity and its possible impact on overall prognosis in IBC. Methods: Clinical and immunological data of IBC patients enrolled in University of Washington IRB approved HER2 vaccine trials was collected and reviewed. 27 patients immunized between 1996–2008 were identified; and 24/27 subjects who received vaccines designed to elicit both CD4+/CD8+ immunity were included in immunologic and survival analysis. The 24 subjects received either a HER2 DNA or HER2 peptide-based vaccine that were admixed with GM-CSF and given intradermally monthly for a total of 3 DNA or 6 peptide vaccines. Immune responses were assessed via IFN-γ ELISPOT at baseline and post-vaccination. Results: All 24 subjects had stage III IBC and median age was 48 (range 34–77). 10/24 (42%) patients had ER/PR+ tumors, 9/24 (37%) had received trastuzumab, and 15/24 (62%) had received multimodality treatment (chemotherapy, mastectomy, radiotherapy). 12/18 subjects (66%) evaluable for immunologic response developed HER2-specific T-cell immunity post-vaccination. Median OS for patients (n=6) not generating HER2-specific immunity was 31 months and median OS for the 12 patients who developed HER2-specific immunity has not been reached at median follow-up of 46 months, (p=0.026). Conclusions: Patients with IBC are able to generate HER2-specific T-cell immunity after HER2 vaccination, and development of HER2-specific immunity may impact survival.

No significant financial relationships to disclose.
Association of the level of HER2/neu (HER2) gene amplification in breast cancer and the magnitude of antigen specific T-cell immunity achieved after HER2 vaccination
Authors: Wallace D. , Disis M. , Coveler A. , Higgins D. , Childs J. , Bates N. , Salazar L. , Slota M. , Dang Y. , Waisman J.
Published: August 2020

3059

Background: Studies have demonstrated that the level of HER2 gene amplification in breast cancer, assessed by fluorescence in situ hybridization (FISH), correlates with favorable clinical response after treatment with trastuzumab. We questioned whether HER2 gene amplification impacted the development of HER2-specific T-cell immunity following immunization with a HER2 vaccine. Methods: Patients with HER2+ stage III or IV breast cancer, treated to complete remission or stable bone only disease, were enrolled in one of two concurrent clinical trials of HER2-specific vaccines. Eligibility criteria between the two studies were similar. Patients received either a plasmid DNA-based vaccine encoding the HER2 intracellular domain or a peptide-based vaccine composed of 3 HER2 class II epitopes. Peripheral blood was assessed for HER2-specific T-cell responses by interferon gamma (IFN-g) ELISPOT prior to, immediately after, and 6 months to 1 year after the end of vaccinations. Both immune response and FISH data were available on 31 patients. Results: Correlation of FISH levels to IFN-g spots/well in evaluable patients revealed the level of HER2 gene amplification was not related to the presence of pre-existent HER2-specific T-cell immunity prior to vaccination (p=0.43), the generation of a HER2-specific immune response after vaccination (p=0.35), or the persistence of the HER2-specific T-cell response (p=0.33). However, the magnitude of the T-cell response achieved was less as HER2 gene amplification increased (p=0.05). Conclusions: The level of HER2 gene amplification in the primary tumor can adversely impact the magnitude of HER2-specific T-cell immunity achieved after vaccination.

No significant financial relationships to disclose.
Anticancer effects of polyadenylic-polyuridylic acid (poly[A:U]) and uncoupling of chemokine receptor signaling: Role of CCR5 and CXCR3
Authors: Conforti R. , Ma Y. , Morel Y. , Paturel C. , Terme M. , Viaud S. , Chaput N. , Andre F. , Kroemer G. , Zitvogel L.
Published: August 2020

3063

Background: Several tumor cells express toll-like receptors (TLRs) which constitute putative therapeutic targets. Methods: To dissect the clinical outcome of the host versus cell autonomous effects of the TLR3 agonist poly(A:U), we took advantage of two murine TLR3 expressing tumor models (melanoma and glioblastoma) that produced large amounts of CCL5 (a CCR5 ligand) and CXCL10 (a CXCR3 ligand) in response to the poly(A:U) and type I IFN in vitro and in vivo. We tested in vivo a triple combination based on vaccine against tumor antigens (V), chemotherapy (C), and TLR3 agonist (poly[A:U]) (T). Results: Single agents (V, C, or T) and combinations of two agents (VC, VT, or CT) failed to improve tumor progression. However, the sequential tritherapy (VCT) significantly retarded tumor growth and prolonged the survival of tumor-bearing C57BL/6 mice. The antitumor effects of VCT (immunochemotherapy) failed to be observed in nu/nu and TRIF-/- mice, indicating the contribution of T cells and TRIF-dependent signals to the therapeutic effect. Knockout of CCR5 improved the efficacy of immunochemotherapy. The VCT combination induced the recruitment of IFNγ+/CD8+/CXCR3+ T lymphocytes supporting the notion that this subset of T cells contributes to the antitumor efficacy of immunochemotherapy. Knockout of the CXCR3 gene annihilated the beneficial effects of VCT. The source of the deleterious CCL5 was the TLR3-activated tumor cells in that stable inhibition of the chemokine production by targeted shRNA CCL5 ameliorated the efficacy of VCT tritherapy. Altogether, 11% of wild-type mice were completely protected from melanoma by VCT sequential regimen. Conclusions: This study supports the notion that poly(A:U) can act on tumor epithelia to promote the release of beneficial CXCL10 for the recruitment of intratumoral CTLs but also the release of deleterious CCL5 acting on host immunosuppressors. Uncoupling chemokine release and/or prior vaccination may enable the CXCR3L-dependent CTL to overrule the CCR5-dependent suppression and may be integrated in future trials using TLR3 agonists.

[Table: see text]
Phase I study of peptide vaccine with chemotherapy in patients with unresectable colorectal cancer
Authors: Yoshimatsu K. , Yokomizo H. , Otani T. , Osawa G. , Ogawa K.
Published: August 2020

3067

Background: RNF43 is a cancer testis antigen expressed in colorectal cancer (CRC) but not in normal organs. RNF43–721 induces HLA A24 restricted cytotoxic T lymphocytes (CTL) against RNF43 expressed target. S-1/CPT-11 chemotherapy (CT) is reported to be obtained the similar result to FOLFOX or FOLFIRI as first-line for advanced CRC. We plan phase I study to evaluate the safety of different doses of RNF43–721 emulsified with Montanide ISA51 in combination with S-1/CPT-11 CT expecting synergistic effect. Methods: Inclusion criteria as follows: HLA A24 positive, pathological CRC, life expectancy > 3 months, WBC>3000/mm3, Hb>10mg/dl, Plt>75000/mm3, creatinine<1.2mg/dl, T. bil.<1.5mg/dl, AST, ALT<3x normal limits, written informed consent. Other malignancy, infection, treatment with steroids and immunosuppressive agents, and HBV, HCV, HIV infection are excluded. The study design is dose escalation of peptide (0.5, 1.0, 3.0 mg) with three patients’ cohort. The study regimen is that oral administration of S-1 at 40 mg b.i.d. for 21 consecutive days followed by a 7-day rest period and intravenous infusion of CPT-11 at a dose of 80 mg on days 1 and 15 are performed with weekly subcutaneous injection of peptide vaccine. Two courses are study periods and there is no restriction of therapy after study. Primary endpoint is safety and secondary are CTL, objective response rate and TTP. Results: Twelve patients (pts) were enrolled and 3 pts canceled treatment due to patient's proposal. In 9 evaluable pts, median age of pts with 7 males and 2 females was 61. Standard chemotherapy for CRC were failed in 8 pts. Systemic toxicities were observed in one pt with grade 2 and others were grade 1. Skin reactions were occurred in 7 pts. No pts were obtained CR and PR, 6 pts were SD and 3 were PD. CTL response was observed in 5 pts. TTP was calculated as 204 days. Conclusions: Treatment with peptide vaccine and S-1/CPT-11 CT was well tolerated. These results encourage further clinical trials of peptide vaccine with standard CT for advanced CRC.

No significant financial relationships to disclose.
Phase I dose-escalation study of XL147, a PI3K inhibitor administered orally to patients with solid tumors
Authors: Shapiro G. , Kwak E. , Baselga J. , Rodon J. , Scheffold C. , Laird A. D. , Bedell C. , Edelman G.
Published: August 2020

3500

Background: XL147 is a selective inhibitor of Class I PI3K isoforms. In preclinical cancer models XL147 is cytostatic or cytoreductive as monotherapy and enhances the efficacy of targeted agents and chemotherapeutics. This open label, Phase 1 dose escalation study assesses the safety, pharmacokinetics, pharmacodynamics, and efficacy of XL147 in advanced solid tumors. Methods: For each 28 day cycle, patients (pts) receive XL147 on Days 1–21 (21/7) or as a continuous daily dose (CDD). Cycle 1 safety data determine dose-limiting toxicities (DLTs). Tumor response is assessed every 8 weeks. Results: As of December 2008, 39 pts have been treated: 36 on 21/7 across 7 dose levels (30–900 mg) and 3 on CDD at 100 mg. At 900 mg, 2 of 3 pts experienced a DLT of reversible grade 3 rash, and the MTD was established as 600 mg based on 15 pts. Drug-related toxicities included grade 3 skin rash (3 pts), grade 3 arterial thrombosis (1 pt), grade 2 transaminase elevation (1 pt), and grade 1 hyperglycemia (4 pts). XL147 exposure increased with dose from 30–400 mg and was similar from 400–900 mg. XL147 reached steady-state plasma concentrations by Day 15–20. Mean t1/2, z at steady-state ranged from 3.7–6.3 days. Doses ≥400 mg yielded exposures that exceeded the EC90 in xenograft models. A trend suggesting augmented food-induced changes in insulin was evident; however, glucose was minimally affected. XL147 reduced levels of phosphorylated PI3K pathway components in PBMCs, hair, skin, and tumor tissues in an exposure-dependent manner. In 2 pts dosed at the MTD, reductions of ≥70% in PI3K pathway signaling were observed in tumor tissue without compensatory upregulation of MEK/ERK phosphorylation. As of December 2008, 6 pts (3 NSCLC, 1 BCC, 1 NHL, 1 PC) continued on study >6 months including 3 >10 months (NHL, NSCLC, BCC). One pt with hormone refractory PC has sustained a normalization of PSA levels through 5 months. Conclusions: XL147 was generally well tolerated with the MTD for the 21/7 schedule defined as 600 mg. The most common drug-related toxicity was skin rash. Inhibition of PI3K pathway signaling has been demonstrated in tumor and surrogate tissues. Prolonged stable disease has been observed.

[Table: see text]
Results of a phase I trial of KX2–391, a novel non-ATP competitive substrate-pocket directed SRC inhibitor, in patients with advanced malignancies
Authors: Adjei A. A. , Cohen R. B. , Kurzrock R. , Gordon G. S. , Hangauer D. , Dyster L. , Fetterly G. , Barrientes S. , Hong D. S. , Naing A.
Published: August 2020

3511

Background: Src kinase is central to the proliferation, apoptosis and metastasis of tumor cells. KX2–391 is a synthetic, orally bioavailable small molecule Src tyrosine kinase signaling inhibitor. KX2–391 is distinct from all other known Src kinase inhibitors in targeting the peptide substrate-binding site and not the ATP-binding site. KX2–391 is the first peptide site targeted tyrosine kinase inhibitor to enter clinical trials. KX2–391 has a much wider spectrum of solid tumor activity in vitro, and is more potent in mouse xenografts, as compared to other multikinase Src/Abl inhibitors. Methods: This multi-center Phase 1 trial utilized the standard 3+3 design to determine the Maximum Tolerated Dose (MTD), safety, and pharmacokinetics (PK) of KX2–391 in pts with refractory solid tumors. Results: To date, 32 pts (12 m 20 f, median age 59 (range 31–78)) have been enrolled in 7 dose cohorts. Dose limiting toxicities (DLTs), which were all reversible within 7 days, occurred in 4 pts and included elevated ALT and AST, neutropenia, and fatigue. 22 pts experienced no Grade 3 or 4 adverse events. Other Grade 1/2 adverse events include: hypokalemia, anemia, elevated AST, fatigue, dyspnea, fever, vomiting, constipation, hematuria, and lymphopenia. The MTD is 40 mg BID on a 3 out of 4 weeks dosing schedule. 7 pts had prolonged stable disease for 4 months or longer including 2 pts with papillary thyroid carcinoma, 2 with carcinoid, and 1 each with prostate, pancreas, and head and neck cancer. Both the prostate and pancreatic cancer pts had dramatic decreases in their biomarkers (PSA went from 205 ng/ml to 39 ng/ml, and CA19–9 went from 38,838 U/ml to 267 U/ml, respectively). The PK profile demonstrated dose-proportionality, a half-life of 4.5 hrs and a Tmax of 1 hr with no evidence of accumulation with multiple doses. Conclusions: KX2–391 has a favorable PK profile, is well-tolerated, demonstrates preliminary evidence of biologic activity and should be further evaluated in Phase II trials.

[Table: see text]

[Table: see text]
Early evidence of tolerability and clinical activity from a phase I study of TRC105 (anti-CD105 antibody) in patients with advanced refractory cancer
Authors: Rosen L. , Gordon M. S. , Hurwitz H. I. , Wong M. K. , Adams B. J. , Alvarez D. , Seon B. K. , Leigh B. R. , Theuer C. P.
Published: August 2020

3518

Background: CD105 (endoglin) is an angiogenic membrane protein that is over-expressed on proliferating vasculature in solid tumors and up-regulated following anti-VEGF therapy. TRC105 is a human/murine chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth via endothelial cell growth inhibition, ADCC, and apoptosis. Methods: The safety and PK of TRC105 were evaluated in patients with refractory cancer. Subjects were to have adequate organ function and no CNS or central thoracic tumors. TRC105 was escalated in cohorts of 3–6 patients to a maximum feasible dose of 1.0 mg/kg i.v. every 2 weeks. Results: 19 ECOG PS 0–1 patients received TRC105 at doses between 0.01–1.0 mg/kg, including 11 men and 8 women aged 37 to 79 years (median 59). One patient experienced dose-limiting toxicity (DLT) at 0.1 mg/kg of grade 4 gastric ulcer bleeding on Day 4 which resolved spontaneously. No other grade 3 or 4 adverse events were reported. Possibly related grade 1–2 adverse events were rare including fatigue, anemia, proteinuria, dysgeusia, diarrhea, flushing, hyperuricemia and intermittent postcoital vaginal bleeding. One patient with castrate-refractory prostate cancer remains on study after 13 months of TRC105 at 0.01 mg/kg with a complete PSA response and bone scan normalization. In addition, 6-month stable disease was seen in a patient with ovarian cancer (CA125 decrease of 16%). Best response also included stable disease (n = 3) and progression (n = 14). Serum TRC105 concentrations expected to saturate CD105 binding sites (> 0.2 ug/mL) were achieved at a dose of 0.3 mg/kg, and concentrations > 10 ug/mL were achieved at 1.0 mg/kg. HAMA became detectable in 1 patient after 3 months of TRC105 therapy. Conclusions: TRC105 is tolerated at doses with evidence of clinical activity. Additional monotherapy and combination studies are planned.

[Table: see text]
Final results of a pharmacokinetic (PK) and pharmacodynamic (PD) phase I trial of ARQ 197 incorporating dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) studies investigating the antiangiogenic activity of selective c-Met inhibition
Authors: Yap T. A. , Frentzas S. , Tunariu N. , Barriuso J. , Harris D. , Germuska M. , Waghorne C. , Li J. , deSouza N. , de Bono J. S.
Published: August 2020

3523

Background: ARQ 197 (ARQ) is a selective non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell proliferation, invasion and angiogenesis. Preclinical data and declines in circulating endothelial cell (CEC) levels in patients (pts) receiving ARQ suggest antiangiogenic potential of c-Met inhibition. Methods: ARQ was administered orally twice daily (bid) to pts with advanced solid tumors. Pre and post-therapy tumor biopsies were mandated for c-Met and FAK immunohistochemical studies during dose escalation (n = 16). CEC enumeration was evaluated. 12 pts are being investigated in the maximum tolerated dose (MTD) expansion cohort with DCE and Diffusion Weighted (DW) MRI. Results: 29 pts (14 F/15 M; mean 54.4 yrs) received ARQ at doses of 100 (n = 3), 200 (n = 6), 300 (n = 16), and 400 (n = 4) mg bid. 3 pts experienced dose limiting toxicities of CTCAEv3 grade (G)3 fatigue (200 mg bid); G3 hand-foot syndrome, G3 mucositis and G3 febrile neutropenia (400 mg bid). This established the ARQ MTD/recommended phase II dose (RP2D) at 300 mg bid. Other toxicities were G1–2, such as fatigue (n = 5); diarrhea, nausea and vomiting (n = 3). Mean AUC0–12h and Cmax increased linearly through the MTD. Statistically significant post-ARQ inhibition of high baseline phosphorylated c-Met and FAK expression in tumor tissue was seen in all dose cohorts confirming target inhibition. Disease stabilization (SD) was seen in 11 pts for up to 23 weeks with tumor regressions up to 12.4%. 13 of 20 pts had post-ARQ CEC declines of up to 100%. In the DCE-MRI cohort to date, preliminary analyses of ktrans histograms from pelvic lesions were consistent with antiangiogenic effects, with a ktrans median reduction of 20.1% on day 7 of ARQ (intrapatient baseline variability: 2.8%). This effect was still present (ktrans median decline: 8.3%) on day 56 of ARQ. Conclusions: ARQ is well tolerated with MTD/RP2D of 300mg bid, linear PK and evidence of phosphorylated c-Met and FAK inhibition. CEC and preliminary DCE-MRI data support the antiangiogenic effects of c-Met inhibition with ARQ. Correlation with other DCE parameters and DW changes will be presented.

[Table: see text]
Phase I trial of PX-866, a novel phosphoinositide-3-kinase (PI-3K) inhibitor
Authors: Jimeno A. , Hong D. S. , Hecker S. , Clement R. , Kurzrock R. , Pestano L. A. , Hiscox A. , Leos R. A. , Kirkpatrick D. L. , Eckhardt S. G. , Herbst R. S.
Published: August 2020

3542

Background: PX-866 is an orally available nanomolar pan-inhibitor of PI-3K whose administration results in antitumor activity and pathway (AKT, S6 and mTOR) inhibition in animal models. Loss of PTEN and/or PI 3K mutations have been associated with enhanced susceptibility to PX-866. PX-866 is being evaluated in a phase 1 clinical trial to determine the MTD, and measure safety, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints in PBMCs and tumor tissue in patients with solid tumors. Methods: Patients with advanced metastatic cancers receive PX-866 orally once daily for 5 of 7 days for 2 weeks in a 28-day cycle. Dose levels of 0.5, 1, 2, 3, 4.5, 6, 8, and 10 mg are planned. PK and PD samples are collected days 1, 2, 5, 8, 12, and 15 of cycle one and days 1 and 12 of cycle two. A PD assay has been developed that utilizes flow cytometry to test the inhibition of S6RP and mTOR in PBMC. Once the MTD of this PX-866 schedule of administration has been identified, an expansion cohort is planned to investigate tumor PD events and correlate tumor and PBMC endpoints with efficacy. Results: Four cohorts (0.5, 1, 2, 3 mg) comprising 12 patients (age 42–74, median PS 1) have completed accrual, with the 4.5 mg cohort actively enrolling. The total number of cycles to date is 30 (median 2, range 1–5+). Abdominal discomfort and mild diarrhea have been possibly associated with PX-866. No drug-related severe adverse events or dose-limiting toxicities have occurred. Of the 6 patients treated in the first 2 cohorts, 3 previously progressing patients had stable disease (SD) as best response and were on study for 105, 147 and 162+ (still active) days. Two patients (squamous cell skin cancer and melanoma) had decrease in pain allowing discontinuation of analgesics. Proof-of-concept PD studies in PBMCs evidenced a dose dependent inhibition of both p-S6RP and p-mTOR levels. Conclusions: PX-866 is a novel oral PI-3K inhibitor that is undergoing development in a clinical trial with built-in PD endpoints. PX-866 has shown to have a mild side effect profile while inducing stabilization of disease in previously progressing cancer patients. Oral PX-866 provides target inhibition even at low drug doses and inhibition is maintained for an extended time following the last dose. Updated clinical, PK and PD results will be presented.

[Table: see text]
Dual epidermal growth factor receptor (EGFR) inhibition: Phase I study combining cetuximab (C225) and erlotinib (E) in advanced solid tumors
Authors: Sangha R. , Ho C. , Beckett L. , Lau D. H. , Lara P. N. , Davies A. M. , Mack P. C. , Koslan G. M. , Holland W. S. , Gandara D. R.
Published: August 2020

3552

Background: The EGFR pathway is implicated in lung tumorigenesis by aberrantly regulating cell proliferation, apoptosis, and invasion. Maximal blockade of the EGFR can be achieved by dually inhibiting the extracellular and intracellular domain with the monoclonal antibody C225 and the tyrosine kinase inhibitor, E. Given preclinical synergy of C225 and E, we hypothesized this combination would be feasible and result in improved therapeutic benefit. Methods: Patients (pts) with advanced solid tumors were enrolled using a standard phase I dose escalation design. C225 was administered IV weekly, with no loading dose, and E given orally daily on a 28-day cycle. Four dose levels were studied: C225 150 mg/m2, E 100 mg; C225 200 mg/m2, E 100 mg; C225 250 mg/m2, E 100 mg; and C225 250 mg/m2, E 150 mg. Dose limiting toxicity (DLT) was defined as: grade (Gr) 4 platelets, Gr 3 platelets with bleeding, febrile neutropenia, ≥ Gr 3 ANC with documented infection, or clinically significant > Gr 3 non-hematologic toxicity. Gr 3 rash based solely on pain or Gr 3 hypersensitivity infusion reactions were not considered DLTs. Results: 18 pts were treated: 13 NSCLC, 3 H&N, 1 pancreas, and 1 invasive thymoma. Characteristics: Age range 41–80, median 62.5; Gender: 7 M; ECOG PS ≤1 = 17; Prior chemo ≤1 = 10. Planned dose escalation was completed without reaching the MTD. The highest dose level was expanded to 6 pts. A single DLT for Gr 3 diarrhea was observed at the second dose level (C225 200 mg/m2, E 100 mg). Gr 3/4 toxicities were: lymphopenia (3), acneiform rash (3), nausea/vomiting (3), pruritis (1), fatigue (1), diarrhea (1), confusion (1), hypomagnesemia (1), hypocalcemia (1), hyponatremia (1), hyperkalemia (1), and anemia (1). Of 13 evaluable pts, 1 PR (NSCLC) and 4 with SD (2 NSCLC, 2 H&N). Median cycles: 2 (1–14) with one NSCLC pt on therapy for 8 cycles and one H&N pt receiving 14 cycles. Biomarker analysis of EGFR polymorphisms, gene copy number via FISH, and protein expression will be presented, along with the mutation status of EGFR and KRAS. Conclusions: 1) Dual EGFR inhibition with C225 250 mg/m2 weekly and E 150 mg daily is feasible, well tolerated, and the recommended phase II dose. 2) Efficacy of this combination in NSCLC is being evaluated in a phase II trial.

[Table: see text]
Axitinib (AG-013736; AG) combined with chemotherapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) and other solid tumors
Authors: Martin L. P. , Kozloff M. F. , Krzakowski M. , Samuel T. A. , Rado T. A. , Tarazi J. , Rosbrook B. , Tortorici M. , Olszanski A. J. , Cohen R. B.
Published: August 2020

3559

Background: AG is an oral, potent and selective inhibitor of VEGFRs 1, 2, 3. Anti-VEGF therapies combined with chemotherapy improve survival vs chemotherapy alone in pts with advanced solid tumors, including NSCLC. This phase I trial assessed AG combined with chemotherapy. Methods: Pts with advanced solid tumors without prior treatment with platins or taxanes received paclitaxel/carboplatin (P: 200 mg/m2 / C: AUC 6 mg*min/mL) every 3 weeks + AG at lead-in doses of 1, 3 or 5 mg BID. AG was increased to 5 mg BID post lead-in. Another cohort of pts with any prior chemotherapy for metastatic disease received AG 5 mg BID + gemcitabine/cisplatin (G: 1250 mg/m2 on days 1 and 8 / Cis: 80 mg/m2 on day 1) in 3-week cycles. For all cohorts, cycle 1 consisted of a 3–5-day lead-in period followed by AG for 18 days. On day 19, AG was held and then continued without interruption on day 3, cycle 2. Following determination of the maximum tolerated doses (MTDs) of AG + P/C or G/Cis, pts with squamous NSCLC were enrolled into an expansion cohort (prior anti-VEGF therapy not permitted) and received AG 5 mg BID + P/C. Dose-limiting toxicities (DLTs), adverse events (AEs), objective response rate (ORR), and pharmacokinetics (PK) were evaluated. Results: A total of 47 pts were enrolled; 26 pts were evaluable in the P/C cohort (including 12 pts with squamous NSCLC) and 21 pts in the G/Cis cohort. The MTD for AG in combination with standard doses of P/C and G/Cis was 5 mg BID. DLTs included fatigue, proteinuria and rash (1 each). Treatment-related AEs included hypertension (42%), diarrhea (35%) and fatigue (35%) in the P/C cohort, and headache (29%), hypertension (29%) and fatigue (24%) in the G/Cis cohort. There was no grade ≥3 hemoptysis among 12 pts with squamous NSCLC. The ORR was 29% and 26% for P/C (n = 24) and G/Cis (n = 19) cohorts, respectively. AG, P, C, G and Cis PK parameters and profiles were similar when administered alone and in combination (eg P: mean (%CV) AUCinf 20,822 (21) and 20,596 (21) ng.h/mL, respectively). Conclusions: AG 5 mg BID can be combined with standard P/C and G/Cis regimens with no apparent overlapping toxicities and unaltered PK. Both combinations have antitumor activity. In pts with squamous NSCLC, AG + P/C was well tolerated with no evidence of grade ≥3 hemoptysis.

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Mass balance, pharmacokinetics, and metabolism of [14C] brivanib (BMS-582664), prodrug of BMS-540215, in subjects with advanced or metastatic solid tumors
Authors: Ganapathi R. , Mekhail T. , Wu C. , Fischer B. , Gong J. , Iyer R. A. , Gan J. , Pursley J. , Patricia D. , Masson E.
Published: August 2020

3566

Background: Brivanib alaninate (BMS-582664, B) is an oral prodrug of BMS-540215, a dual tyrosine kinase inhibitor of VEGFR and FGFR signaling pathways which are important for angiogenesis and tumor growth. The recommended phase II/III dose of B is 800 mg daily. Methods: A two-part, open-label, single-dose study was conducted in subjects with advanced or metastatic solid tumors. Part A represented the period for assessment of the pharmacokinetics (PK), metabolism, and elimination of B, In part A, subjects received a single oral dose of 800 mg [14C]-labeled B containing 100 μCi of total radioactivity (0.125 μCi/mg). Blood was collected at selected time points for analyses of PK, biotransformation, and total radioactivity over a 10-day period. Complete urinary and fecal output was collected over the 10-day period or until discharge, and analyzed for total radioactivity and biotransformation. Part B began when subjects completed Part A. Part B subjects received B administered orally at a dose of 800 mg once daily starting on approximately Day 15 to 17 of study. Subjects continued in this study until disease progression or unacceptable toxicity. Results: 4 subjects (2 NSCLC, 1 ovarian, 1 renal cell carcinoma) were treated with B in both parts A & B. B was tolerable with few G3/4 AEs (increased fatigue, 1 event, cognitive disturbance, 1 event). The results revealed that B is completely converted to active moiety, BMS-540215, after oral administration. BMS-540215 is extensively metabolized in humans. Elimination is primarily via the feces. Following a single oral dose of [14C]-labeled B, approximately 12% and 82% of the administered radioactivity was recovered in the urine and feces, respectively, within 10 days. BMS-540215 accounted for 0.00% and 7.4% of the administered dose in urine and feces, respectively, with the remainder of the dose being minor metabolites. The mean terminal t1/2 of BMS-540215 was 14 hours. Conclusions: After oral administration of single 800 mg oral doses of [14C] B, BMS-540215 was found to be the major active circulating moiety in plasma (22.5%). BMS-540215 is primarily eliminated via metabolism. [14C]-labeled B formulation was well tolerated with no AEs leading to the discontinuation of any subject.

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Translational proof of mechanism (PoM) for sorafenib with bevacizumab: Endpoint analysis and clinical activity
Authors: Azad N. S. , Henning R. , Yu M. , Davidson B. , Figg W. D. , Calvo K. , Venkatasen A. , Annunziata C. , Meltzer P. , Kohn E.
Published: August 2020

3574

Background: We hypothesized that molecular targeting of tumor and its microenvironment with rational combination therapy would yield improved outcome. Bevacizumab (B) is a monocolonal antibody to vascular endothelial growth factor (VEGFF) and sorafenib (S) is a small molecule inhibitor of the VEGF receptor-2 and RAF-kinase.We have previously reported that S 200mg bid with B 5mg/kg q2wk resulted in partial responses and prolonged disease stabilization (ovarian cancers, renal cell cancer, leiomyosarcoma). Serial tumor biopsies were obtained for translational proof of mechanism analysis. Methods: Percutaneous core biopsies of metastatic sites were obtained at baseline, after 2wk of S (group A) or B (group B), and at 6wks (2 wk into S+B combination therapy). Tissue was used for: lysate array (TLA) proteomic analysis of signaling proteins, IHC for CD31, VEGF, and Ki67, Raf/Ras mutation, and SNP analysis. Results: 18 sets of 3 biopsies were obtained, assessed for morphologic response (MR; decrease to <60% viable tumor seen), and processed for TLA and IHC. 11 pts had morphologic response including all 4 PR and 6/12 SD pts. Greater reduction in change in phospho(p)-ERK was seen at 2wk in group A pts (starting with sorafenib only) (p = 0.003). 9/11 MR pts had inhibition of ERK or AKT activation (p < 0.03). OvCa pts were more likely to have reduction in bRaf (p = 0.02). Pts in group B (starting with bevacizumab only) had lower microvessel density as measured by CD31 IHC (p = 0.05) at 2 wks; there was also a trend to lower VEGF expression by IHC in that group.These effects were muted at time 3, after combination treatment. No relationships to clinical outcomes were found, every pt had at least 1SNP in >1 tested gene; there were no Ras mutations and 1 V600KRaf mutation . Conclusions: These exploratory results demonstrate proof of mechanism in the tumor and its microenvironment for the combination of S and B. Randomization of initial exposure for the first 4 wks allowed interrogation of the role of the independent agents; the Raf/ERK axis was inhibited by S treatment first and there was reduction in tissue angiogenesis markers with B first. The molecularly targeted combination of sorafenib and bevacizumab is biologically active and on target. Phase II studies in multiple tumor types are ongoing.

No significant financial relationships to disclose.
Clinical, pharmacokinetic (PK), and pharmacodynamic findings from a phase I trial of an Eg5 inhibitor (AZD4877) in patients with refractory acute myeloid leukemia (AML)
Authors: Borthakur G. , Faderl S. , Ravandi F. , Padmanabhan S. , Stock W. , Wu K. , Li J. , Curt G. , Tallman M. , Minden M.
Published: August 2020

3580

Background: AZD4877 is a potent, specific inhibitor of Eg5 (kinesin spindle protein). The only known function of Eg5 is to separate the centromeres during mitosis. Eg5 inhibition is thus specific for dividing cells, resulting in monoastral mitotic spindles (monoasters) and apoptotic cell death. Preclinically, hematologic tumor cell lines were generally more sensitive to AZD4877 than those derived from solid tumors. Methods: AZD4877 was administered IV daily x 3 as induction for up to 2 cycles, followed by consolidation (daily x 2) for up to 4 cycles. Eligibility criteria were standard. Results: Cohorts of 3–6 patients (pts) were treated at doses of 2, 4, 7, 10, 13, 16, and 18 mg/day. To date, 24 evaluable pts have received 33 induction and 3 consolidation cycles of treatment. Monoasters were detected at all dose levels evaluated (2, 7, 10, 13, and 18 mg/day). The T1/2 of AZD4877 ranged from 26 to 42 hr; PK were linear and drug levels non-cumulative. Myelosuppression, the dose limiting toxicity (DLT) in solid tumor studies, was not considered a DLT in this trial. Mucositis was the DLT at 18 mg/day; with 1 pt developing Gr 3 palmar-plantar syndrome at this dose. Bone marrow biopsies were undertaken at screening and as clinically indicated. In pts with evaluable biopsies, marrow blasts decreased by 60–80% in 2 pts, and by 30–50% in 3 pts, with no response in 3 pts. Conclusions: Enrollment is ongoing at 16 mg, the likely Phase 2 dose. Preliminary results suggest possible clinical activity in AML. An expansion phase at the MTD is planned.

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Advancement to the clinic of an RNAi therapeutic for solid tumors
Authors: Bumcrot D. , Toudjarska I. , Judge A. , Brodsky J. , Ambegia E. , Buck T. , Racie T. , Jeffs L. , MacLachlan I. , Gollob J. , Sah D. W.
Published: August 2020

3585

Background: Malignancies of the liver, including primary (hepatocellular carcinoma) and secondary (metastatic) tumors, represent a significant unmet medical need. We are developing a therapeutic for solid tumors involving the liver that is comprised of lipid particle-formulated short interfering RNAs (siRNAs) targeting VEGF and the mitotic kinesin, KSP (Eg5). For each target, potent siRNA duplexes were selected following extensive screening in tissue culture cells. Efficacy was demonstrated in a mouse liver tumor model. Methods: To assess efficacy in vivo, a stable nucleic acid lipid particle (SNALP) formulation was developed based on similar formulations previously shown to silence liver-expressed genes via systemic administration in multiple species. A SNALP-formulated combination of the KSP and VEGF siRNAs (referred to as ALN-VSP01) was tested in an orthotopic liver tumor model in which human hepatoma cells (Hep3B) are implanted directly into the livers of immunocompromised mice. Results: Intravenous administration of ALN-VSP01 leads to dose-dependent inhibition of both KSP and VEGF expression in established liver tumors. This was accompanied by the formation of numerous aberrant mitotic figures (“monoasters”) in tumor cells indicative of the pharmacologic inhibition of KSP. In addition, tumor growth was significantly inhibited by a course of ALN-VSP01 treatment, and ALN-VSP01 treatment provided a clear survival benefit even when treatment was initiated in animals with a significant tumor burden. As a control, a SNALP-formulated siRNA targeting Luciferase was administered and shown to have no effect in these studies. Conclusions: Systemic administration of ALN-VSP01 exhibited clear efficacy in a mouse orthotopic liver tumor model. Clinical testing of ALN-VSP01 is expected to initiate in early 2009.

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Interim efficacy analysis of the French Intergroup R98 trial comparing 5FU-leucovorin alone or with irinotecan (CPT-11) in resected stages II-III rectal cancers
Authors: Piedbois P. , Ychou M. , Zawadi A. , Douillard J. , Guérin-Meyer V. , André T. , Dupuis O. , Rougier P. , Faroux R. , Quinaux E. ,   AERO, GERCOR, FFCD, and FNCLCC Intergroup
Published: August 2020

4015

Background: The R98 trial tests the hypothesis that irinotecan (CPT-11) combined with 5FU/LV is superior to 5FU/LV alone to prevent recurrence or death in resected stages II-III rectal cancers. Methods: 600 pts were planned to be randomized between 5FU/LV (control arm) or 5FU/LV + CPT-11. Recruitment was slow, with only 357 pts included in the study between 03/1999 and 12/2005 (178 in control arm and 179 in CPT-11) at which time the IDMC recommended closure of accrual. The primary endpoint was disease free survival (DFS), relevant events being death (whatever its cause), local or distant recurrence, and any new primary cancer. The trial was stratified by choice of control arm: either a Mayo-Clinic regimen (A: LV 20 mg/m2, 5FU 425 mg/m2 bolus days 1–5, repeated at d29, d57, d92, d127 and d162) or a LV5FU2 regimen (A’: LV 200 mg/m2 over 2-hour, 5FU 400 mg/m2 bolus and 600 mg/m2 22-hour infusion, d1–2, q2w for 12 cycles), depending on centre decision. The experimental arm (B) consisted of LV5FU2 + CPT-11 180 mg/m2 d1 of every cycle. Results: Safety analysis was reported last year (P. Piedbois et al. Proc. ASCO 2008). We present here a first interim analysis of efficacy on half the numbers of events planned per protocol. Median follow-up is 55 months. Pretreatment characteristics were well balanced between the groups; median age 62 years, stage II in 32% of pts. 68% of pts received preoperative RT, and 80% had sphincter conservation. There was a trend in favor of 5FU/LV + CPT-11 in terms of DFS (77 vs 62 events in control and CPT-11 arms, hazard ratio=0.75, p=0.089) with similar effect in the Mayo-Clinic stratum (31 vs 25 events, hazard ratio=0.77) and in the LV5FU2 stratum (46 vs 37 events, hazard ratio=0.74). Conclusions: This interim efficacy analysis shows a trend in favor of 5FU/LV + CPT-11. If performed when at least 220 events are observed (projected in 2010), the next efficacy analysis would have a conditional power of about 60% to detect a true benefit of 5FU/LV + CPT-11 if the treatment effect remained the same as observed today. Study supported by Pfizer, France.

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High epiregulin (EREG) gene expression plus K-ras wild-type (WT) status as predictors of cetuximab benefit in the treatment of advanced colorectal cancer (ACRC): Results from NCIC CTG CO.17—A phase III trial of cetuximab versus best supportive care (BSC)
Authors: Jonker D. J. , Karapetis C. , Harbison C. , O’Callaghan C. J. , Tu D. , Simes R. J. , Xu L. , Moore M. J. , Zalcberg J. R. , Khambata-Ford S.
Published: August 2020

4016

Background: Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), improves overall survival (OS) and progression free survival (PFS) in patients with K-ras WT chemotherapy refractory ACRC. Gene expression of the EGFR ligand epiregulin (EREG) may further predict benefit from cetuximab. Methods: CRC tumour samples were analyzed from a phase III clinical trial of cetuximab plus BSC vs BSC alone (NEJM 2007; 357(20)). EREG gene expression was detected in tumour-derived genomic RNA blinded to clinical outcome by quantitative real time-PCR. Using a pre-specified threshold for “high” EREG derived from a prior study (CA225–045), the predictive effect of (1) high vs low EREG among K-ras WT and (2) high EREG/K-ras WT status (“Combimarker”) versus all other patients on OS and PFS was examined using a Cox model with tests for treatment-biomarker interaction. Results: Both EREG gene expression levels and K-ras mutation status were ascertained in 385 (67%) of the total study population (193 cetuximab, 192 BSC). In the K-ras WT subset, OS was better for cetuximab than BSC among patients with high EREG (HR 0.43; p<0.0001) but not for low EREG patients (HR 0.77, p=0.28). The test for interaction showed a non-significantly larger treatment effect in the high EREG group (HR 0.62, p=0.13). High EREG AND K-ras WT status (“Combimarker”) was present in 139 (36%). Within the Combimarker positive group the median PFS was 5.4 vs 1.9 months (HR, 0.31; p<0.0001), and median OS 9.8 vs 5.1 months (HR, 0.43; p<0.001) in the cetuximab vs BSC arms, respectively. In the rest (n=246, 64%) cetuximab was not associated with improved PFS (HR, 0.82; p=0.12) or OS (HR, 0.90; p=0.45). The test for treatment-Combimarker interaction showed a larger cetuximab effect on OS (HR 0.52; p=0.007) and PFS (HR 0.49; p=0.001) in the Combimarker positive group. Conclusions: In the setting of pre-treated ACRC, patients with both high EREG gene expression and K-ras wild- type status may benefit from cetuximab therapy. Determination of EREG gene expression levels should be prospectively evaluated in patient selection for EGFR targeted therapy.

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