bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I study of a CanAg-targeted immunoconjugate, huC242-DM4, in patients with Can Ag-expressing solid tumors
Authors: Mita M. M. , Ricart A. D. , Mita A. C. , Patnaik A. , Sarantopoulos J. , Sankhala K. , Fram R. J. , Qin A. , Watermill J. , Tolcher A. W.
Published: March 2020

3062

Background: HuC242-DM4 is a novel, targeted anti-cancer agent in development for the treatment of CanAg-expressing tumors such as carcinomas of the colon and pancreas. The compound is formed by the conjugation of the potent cytotoxic maytansinoid drug, DM4, to the humanized monoclonal antibody, huC242. This agent was highly active across a broad spectrum of CanAg-expressing human tumor xenograft models. Methods: Patients were enrolled with metastatic or inoperable colorectal, pancreatic, and other CanAg-expressing tumors who have failed standard therapy (about 95% of pts. had received = 4 prior chemotherapy regimens). Results: Thirty patients were treated with huC242-DM4, receiving a single intravenous (IV) infusion once every three weeks. Cohorts of 3 patients initially were enrolled on each dose level. Patients have received huC242-DM4 at 18, 36, 60, 90, 126, 168, 223, and 297 mg/m2. To date, dose limiting toxicity (DLT) was experienced by two of six patients treated at the 223 mg/m2 dose level during their second cycle of treatment. The patients experienced decreased visual acuity, corneal deposits and keratitis. Both patients were subsequently treated with lubricating eye drops. At present, these adverse events have markedly improved in one patient, while the other patient has completely returned to baseline. Of 10 patients treated at the168 mg/m2 dose level (including two patients who were dose reduced to 168 mg/m2), seven patients have received at least two cycles of treatment. One patient had grade 3 diarrhea and dehydration during his second cycle at 168 mg/m2. The latter improved with intravenous fluids. Preliminary pharmacokinetic data reveal a half-life of huC242-DM4 of about 5 days in patients with low plasma CanAg levels. In patients with high plasma CanAg levels (>900 units/mL), clearance of huC242-DM4 is increased. There has been no clinically significant myelosuppression and no formation of antibody to humanized antibody (HAHA) or drug (HADA). One patient had a 36% decline in CEA (not associated with tumor shrinkage). Conclusions: HuC242-DM4 was well tolerated at the 168 mg/m2 dose level. The MTD is not yet defined and approaches to prevent /ameliorate ocular toxicity are planned.

No significant financial relationships to disclose.
Vγ9Vδ2 T (γδ) lymphocytes: a promising approach for immunotherapy of solid tumors
Authors: Squiban P. J. , Bompas E. , Bennouna J. , Levy V. , Sicard H. , Lafaye de Micheaux S. , Viey E. , Salot S. , Tiollier J. , Calvo F.
Published: March 2020

3064

Background: The Vγ9Vd2 T (γd) blood lymphocyte subset has a strong cytotoxic potential and can be selectively activated with chemically-synthesized, structural analogues of non-conventional antigens like BrHPP (IPH1101). Their proliferation requires low dose of Interleukin-2 (IL-2). Methods: We developed several in vitro and in vivo models to assess the immunotherapeutic potential of IPH1101-activated γd cells: - Direct cytotoxicity assays on patient-derived primary tumor cell lines - Extensive pharmacodynamics in the non human primate (NHP) - Small scale in vitro amplification assays for IPH1101-sensitive patient pre-selection Then, two Phase I clinical trials were performed in solid tumor patients: - Autologous cell therapy with ex vivo IPH1101- expanded γd cells (1, 4 or 8.109 cells) - Direct administration of IPH1101 (200 to 1800 mg/m2 i.v.) and low dose IL-2 (106 U/m2 s.c.). Results: In NHP, IPH1101 and low dose IL-2 induce early pro-inflammatory cytokine release and dose-dependent γd cell amplification in peripheral blood. In vitro, mRCC tumor cells are efficiently and selectively killed by autologous γd cells. In Phase I clinical trials, both ex vivo expanded γd cells and IPH1101 were well tolerated. - Cell therapy-related AEs included mainly gastrointestinal disorders, flu-like symptoms and hypotension. Six patients showed stabilized disease. Median duration of stabilization was 25.7 weeks. 2 pts treated with 4.109 or 8.109 cells showed substantial tumor shrinkage at the 14-week evaluation (-22% and -48%, respectively). - When IPH1101 was administered with low dose of IL-2, a significant increase of blood γd T cells was observed (up to 240 times the basal values) and in terms of clinical activity assessment, among the evaluable mRCC population (n=15), 8 patients presented disease stabilization for more than 35 weeks, including 6 for more than 51 weeks. Conclusions: For the first time, a specific γd immunotherapy was fully developed and led to Phase I clinical trials. It has been found well tolerated. Encouraging signs of disease stabilisation in mRCC patients suggest that γd may have a role in the treatment of cancers resistant to conventional therapies. A phase 2 is ongoing in mRCC patients.

No significant financial relationships to disclose.
Phase II trial of a 10-epitope CTL vaccine, EP-2101, in metastatic NSCLC patients
Authors: Brown S. , Cunningham C. , Mary G. , Morse M. , Greco F. A. , McCune D. , Khong H. , Steis R. , Mills B. , Ishioka G. , Bender J.
Published: March 2020

3068

Background: The 10-peptide EP-2101 vaccine is designed to induce multi-specific CTL responses against epitopes in CEA, p53, HER-2/neu and MAGE 2/3. Seven epitopes are modified for enhanced MHC binding or heteroclitic T-cell activation including the previously described CAP1–6D heteroclitic analog and 2 epitopes are native wild-type (WT) sequences. Also included is the helper epitope PADRE. We report here immunogenicity results from a Phase II trial of the EP-2101 vaccine. Methods: 66 HLA-A2+ good performance patients with Stage IIIB/IV NSCLC were enrolled. Patients received 6 induction doses (0.5 mg/epitope) q3 wks followed by maintenance treatments at 2–3 month intervals. Endpoints included survival and induction of immune responses. CTL responses in peripheral blood MNC were measured after a 10 day in vitro stimulation with peptide followed by an IFNγ ELISPOT assay. Results: 33 patients completed induction and the first 11 patients were monitored for CTL against all vaccine epitopes. Seven of 11 patients generated responses against ≥ 4 epitopes after 3 and 6 vaccine doses and 8 patients generated CTL against ≥ 3 WT vaccine epitopes and WT sequences of vaccine analogs. Responses ranged between 10–50 spots/5x10e4 cells with stronger responses of >100 spots observed. All 9 vaccine epitopes were immunogenic in at least 1 patient. CTL responses against epitopes were maintained at Wk 30 and/or Month 9 in 7 of 8 patients. At Month 12, 2 of 4 patients also had detectable CTL against the vaccine. The 22 remaining patients were monitored against 5 representative vaccine epitopes. 13 of these patients generated CTL responses to ≥ 2 epitopes and 7 patients generated responses to ≥ 3 epitopes. Th-cell responses against PADRE measured with a direct IFNγ ELISPOT assay were observed in 18 of the 33 patients tested. Toxicities attributable to vaccine were mild and consisted mostly of injection site reactions. Follow-up for survival is ongoing. Conclusions: The peptide vaccine EP-2101 is well-tolerated and induces broadly-specific CTL responses in metastatic NSCLC patients.

[Table: see text]
Activity of MVA 5T4 alone or in combination with either interleukin-2 (IL-2) or interferon-α (IFN) in patients (Pts) with metastatic renal cell cancer (MRCC)
Authors: Cao A. , Hernandez-McClain J. , Willis J. , Harrop R. , Shingler W. , Chikoti P. , Drury N. , Amato R.
Published: March 2020

3069

Background: MVA 5T4 consists of the highly attenuated modified Vaccinia Ankara virus containing the gene encoding the human TAA 5T4. Ninety percent or more of RCCs overexpress the 5T4 antigen. A series of clinical trials were conducted to evaluate the effectiveness of MVA 5T4 as a single agent or in combination with Interleukin-2 or Interferon Alpha 2B. Methods: Eligibility: pathologic diagnosis of clear cell or papillary RCC, progressive measurable metastases, any prior therapy, adequate physiologic parameters, Karnofsky performance status (KPS) = 80%, and no active CNS involvement. A regimen of MVA 5T4 alone or in combination with IFN or IL-2 was given. Results: A total of 41 patients received MVA 5T4 alone or in combination. 33 patients received MVA 5T4 with low dose IL-2 or IFN. 23 pts had clear cell; 12 papillary; 5 mixed clear cell; and 1 mixed papillary. 19 pts continue to receive therapy. 2 pts (both clear cell RCC) developed complete responses, 3 pts/partial responses (2 clear cell, 1 papillary) 8 pts/stable for 3+months and 6 pts are too early to be staged at this time. Median duration of therapy is 3.0+ (1+-13+) months. Conclusion: Although comparable antibody response were observed in papillary and clear cell histotypes, clear cell patients appeared to be more likely to respond in terms of clinical benefit parameters, to be presented. Of note is that preliminary analysis of clear cell patients suggests a relationship between the anti-5T4 immune response and tumor response. With the immunological potency and encouraging clinical activity, the future research will focus on the phase 3 randomized, double-blind, placebo controlled parallel group study to investigate whether MVA 5T4, added to first line standard of care therapy, prolongs the survival of patients with locally advanced or metastatic clear cell as well as studies to further optimize MVA 5T4 potency.

[Table: see text]
A xenogeneic PSMA DNA vaccine for patients (pts) with non-castrate metastatic (NCMPC) and castrate metastatic prostate cancer (CMPC)—A phase I trial of proof of principle
Authors: Slovin S. , Gregor P. , Wolchok J. , Pedraza A. , Orlandi F. , Jefferson M. , Jefferson M. , Fernandez C. , Rudolph J. , Houghton A. , Scher H.
Published: March 2020

3073

Background: Prostate Specific Membrane Antigen (PSMA) represents a target for both primary and metastatic prostate cancer and an anti-angiogenic approach for other solid tumors. Antitumor effects in PC have been observed using autologous dendritic cells pulsed with PSMA peptides. This is a pilot phase I trial of vaccination with a DNA encoding PSMA in patients with PC. The objective was to determine the safety and immunogenicity of vaccination with the genes encoding for mouse and human PSMA in patients with recurrent disease. The hypothesis was that xenogeneic DNA encoding a xenogeneic homologous antigen was a more potent immunogen than self DNA. Methods: Thirty-six HLA-A0201+ pts with either NCMPC or CMPC were randomly assigned to vaccination with either xenogeneic (mouse) or human (self) PSMA DNA delivered i.m. via a high pressure delivery system at 100μg, 1,500μg or 4,000μg every 3 weeks for 3 immunizations. Those pts randomized initially to receive human PSMA DNA received 3 immunizations with mouse PSMA DNA at three week intervals. Sera and peripheral blood mononuclear cells were analyzed for humoral and T cell responses Results: Twenty-nine of 36 pts were evaluable having received all six vaccines. Nine remain active without disease progression or significant change in PSA logslope. One of 6 pts treated at the 4,000μg cohort has been followed by > 92 weeks; at the 1,500μg cohort 1 of 2 pt has been monitored for > 110 weeks; and 1 pt at the 100μg dose has remained on study for > 169 weeks. No high titer antibodies against PSMA were detected by ELISA or FACS against 3T3 fibroblasts transduced to express PSMA. Conclusions: The vaccine was safe at all dose levels without evidence of autoimmune reactivity. While antibodies against PSMA were not detected, studies are ongoing to examine T cell responsiveness. The majority of pts who remain on study were treated at 4,000μg dose level which appears to be the optimal dose. Supported by The Prostate Cancer Foundation and MSKCC Prostate Cancer SPORE

No significant financial relationships to disclose.
A multi-centre, open-label study to assess the safety of Stimuvax (BLP25 liposome vaccine or L-BLP25) in non-small cell lung cancer (NSCLC) patients (pts) with unresectable stage III disease
Authors: Soulieres D. , Smith C. , Ellis P. M. , Murray N. , Jasas K. , Maksymiuk A. , Goss G. , Falk M. H. , Butts C.
Published: March 2020

3075

Background: L-BLP25 is an innovative cancer vaccine that incorporates a synthetic MUC1 lipopeptide in a liposomal delivery system. L-BLP25 is expected to elicit an immune response to cancer cells that express MUC1. Previous clinical studies have demonstrated that L-BLP25 has the potential to extend survival of pts with stage IIIB locoregional NSCLC (Butts C et al., JCO 2005; 23:6674–6681). The present ph I-II study was designed to assess the safety of the current formulation of L-BLP25 using a monophosphoryl lipid A in pts with unresectable stage IIIA and stage IIIB NSCLC. Methods: Pts with stable disease or an objective response to upfront radical therapy with chemoradiation for unresectable stage III NSCLC, plus ECOG 0–1 were eligible. All pts were vaccinated according to a previously described schedule (1). Maintenance immunizations were administered every 6-wks until disease progression. Primary and secondary endpoints were safety and survival respectively. Results: Twenty-two pts were recruited at 7 sites in Canada. 16 pts were evaluated for this interim safety analysis (8 stage IIIA, 8 stage IIIB, median age; 57, ECOG 0 56%, concurrent chemotherapy; 93.8%). Thirteen pts had a partial response and 3 had stable disease following chemoradiation. Thirteen pts experienced an adverse event (AE) during the first 4 vaccinations of which 7 pts had a L-BLP25 related adverse event. Grade 1/2 AEs related to L-BLP25 ≥10% included fatigue, dyspnea, insomnia, anorexia, headache, diarrhea, paresthesia, abdominal pain, influenza-like illness, urinary tract infection and peripheral neuropathy. No pts discontinued L-BLP25 due to an AE and no grade 3/4 AEs related to L-BLP25 were reported. Six pts (37.5%) had an injection site reaction. As of September 2006, 10 pts were still on study treatment. Conclusions: This formulation of L-BLP25 was well tolerated and the side effect profile was similar to that seen in previous studies (1). A controlled global multi-center phase III trial is underway to further evaluate L-BLP25 in this patient population.

No significant financial relationships to disclose.
Vaccination with a CEA epitope mimic leads to reduced growth of tumor transplants
Authors: Brämswig K. , Knittelfelder R. , Gruber S. , Riemer A. B. , Kammerer R. , Zimmermann W. , Horvat R. , Zielinski C. C. , Scheiner O. , Jensen-Jarolim E.
Published: March 2020

3076

Background: The carcinoembryonic antigen (CEA) is a glycoprotein which is overexpressed on nearly 50% of all human tumors. We aimed to establish an active immunotherapy by replacing the poorly immunogenic glycoprotein with highly immunogenic peptides. Methods: Col-1 is a monoclonal antibody directed against CEA on tumor cells. To generate structural mimics of the Col-1 epitope, we used the Col-1 antibody and the biopanning method in order to select immunreactive peptide mimotopes from random phage libraries. Subsequently, immunogenicity of a selected mimotope was examined in BALB/c mice. We assessed antibody-dependent cytotoxicity (ADDC) and complement-dependent cytotoxicity (CDC) mediated by the induced antibodies on CEA expressing HT29 cells. Furthermore, after immunisation the BALB/c mice were transplanted subcutaneously with Meth-A/CEA tumor cells. Results: All peptides selected were exclusively recognized by the anti-CEA antibody. In addition, true mimicry of the peptides with the natural antigen was confirmed by competition ELISA using purified human CEA. The best mimotope was chosen for synthesis in a multiple antigenic peptide (MAP) configuration rendering, therefore, a multiple antigenic mimotope (MAM). BALB/c mice immunized with the MAM developed antibodies against the immunogen and the original antigen CEA. In vitro, the anti-mimotope antibodies were capable of inducing high specific lysis of CEA-expressing HT29 cells via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Moreover, after s.c tumor transplantation no tumor growth was seen in MAM immunized mice, compared to the groups receiving a control mimotope or the naïve group. The CEA-mimotope immunized group showed a capsuled necrotic region without tumor cells but granulocytes and limited vascularisation. The non treated group showed tumor cells in different proliferation stages and neovascularisation. Conclusions: We conclude that the Col-1 epitope of the glycoprotein CEA can be translated into an immunogenic peptide mimic. The mimotope-induced antibodies recognize CEA and do effectively inhibit growth of CEA positive tumors. Based on these findings we suggest that generated mimotopes are candidates for active immunotherapy of CEA- expressing tumors.

No significant financial relationships to disclose.
Dendritic cell based vaccine therapy of melanoma
Authors: Petenko N. N. , Mikhaylova I. N. , Chkadua G. Z. , Ogorodnokova E. V. , Vishnyakova L. Y. , Hatirev S. A. , Cheremushkin E. A. , Kadagidze Z. G. , Demidov L. V. , Baryshnikov A. Y.
Published: March 2020

3077

Background: Vaccination with dendritic cells (DC) expressing tumor antigens is considered to be a possible strategy to induce anti-tumour immune responses in treatment of melanoma. Methods: 42 stage III and IV melanoma patients were enrolled into the study receiving autologous monocyte-derived DCs primed with autologous tumor lysate. DCs displayed mature phenotype. 75% of recruited pts had disease progression after conventional treatments modalities. Pts demographic characteristics wear: age 26–82 years (mean 54), male/female ratio = 24/18. Arm A included 17 pts treated with DC vaccine in therapeutic regimen (III stage - 2 pts, IV stage - 15 pts). Arm B consisted of 25 pts receiving DC vaccine after radical metastasectomy (III stage - 10 pts, IV stage - 15 pts). DC were administered s.c. q 2–4 weeks until disease progression in a dose of 1,0–5,0x10(6) cells. Pts who received = 4 vaccinations were evaluated, totally - 33 pts (79%) were considered evaluable. The vaccine therapy was evaluated for safety, tolerability and clinical effectiveness. Results. DCs vaccine was safe and well tolerated. Toxicity included flu-like syndrome (1 grade CTC), transitory hyperemia and itching in the sites of injections (1 grade CTC). 13 of 17 pts were evaluable in arm A, they received 210 vaccinations (from 4 to 21 per pts, mean 10,5). We observed 15,4% overall clinical response (1 complete and 1 partial response) and 38% stabilization of disease (lasting = 2 mos). 1- year survival, median survival were 42,5% and 9,5 mos, respectively. Follow-up 4–39+ mos. Among 20 evaluable pts in arm B who received 205 vaccinations (from 4 to 38 per pts, mean 15,8) median time to progression was 10 mos, 1-year survival - 84%, at a median follow- up of 12 mos (3–20+) disease free survival was 45%. Conclusion: DCs vaccine therapy is safe and lacks serious adverse effects. Melanoma pts with regional and distant metastasis demonstrated moderate clinical effectiveness in response to specific vaccine therapy.

No significant financial relationships to disclose.
Identification of sensitivity markers for BMS-536924, an inhibitor for insulin-like growth factor-1 receptor
Authors: Huang F. , Hurlburt W. , Hafezi R. , Han X. , Chen J. , Carboni J. , Attar R. M. , Helman L. , Clark E. , Dongre A.
Published: March 2020

3506

Background: Insulin-like growth factor-1 receptor (IGF-1R) signaling is an important regulator of mitogenesis, transformation to the oncogenic phenotype and anti-apoptotic effects in malignant cells. Over-expression of IGF-1R, seen in many tumors, may confer a growth advantage or drug resistance. A potent small-molecule inhibitor (BMS-536924) of IGF-1R tyrosine kinase showed anti-tumor activity in sarcoma, prostate, colon and pancreatic tumor models. One of the integral goals in the development of BMS-536924 as a cancer therapeutic is to identify molecular biomarkers predictive of response to the drug that ultimately will aid in selecting the patients who are most likely to benefit. Methods: The sensitivity (IC50) to BMS-536924 was determined for a panel of 29 pediatric sarcoma and neuroblastoma cell lines. Both microarray and LC/MS based protein profiling were utilized to analyze the baseline gene or protein expression level. Drug treatment studies were performed using two rhabdomyosarcoma cell lines, Rh41 (sensitive to BMS-536924) and Rh36 (resistant to the drug) to identify markers that are modulated by BMS-536924. Results: (1). Sixteen out of the 29 cell lines were highly sensitive to BMS-536924; candidate markers that correlated with the sensitivity to BMS-536924 were identified by gene expression and protein profiling. (2). Histological correlation was also discovered, with specific subtypes of sarcoma having a low IC50 to BMS-536924. (3). Pathway analysis noted that some major candidate markers are common key steps in the EGF-R pathway and the IGF1-R pathway. This observation of cross-talk between the two pathways led to the hypothesis of synergy with combined inhibition of both pathways. Combination studies of BMS-536924 and EGFR inhibitors were performed and synergism was observed. (4). Markers modulated by BMS-536924 in a sensitive cell line were identified. Conclusions: This work has identified candidate markers correlating to BMS-536924 sensitivity in vitro. The possible mechanism of synergistic activity of IGF1-R and EGFR inhibitors will be presented.

No significant financial relationships to disclose.
Circulating tumor cells expressing the insulin growth factor-1 receptor (IGF-1R): Method of detection, incidence and potential applications
Authors: de Bono J. S. , Adjei A. , Attard G. , Pollak M. , Fong P. , Haluska P. , Roberts L. , Chainese D. , Terstappen L. , Gualberto A.
Published: March 2020

3507

Purpose: To detect IGF-1R on circulating tumor cells (CTCs) as a biomarker in the clinical development of a monoclonal human antibody, CP-751,871, targeting IGF-1R. Experimental Design: An automated sample preparation and analysis system for enumerating CTCs (Celltracks) was adapted for detecting IGF-1R positive CTCs with a diagnostic antibody targeting a different IGF-1R epitope to CP-751,871. This assay was utilized in three phase I trials of CP-751,871 as a single agent or with chemotherapy and was validated using cell lines and blood samples from healthy volunteers and patients with metastatic carcinoma. Results: There was no interference between the analytical and therapeutic antibodies. CP-751,871 was well tolerated as a single agent, and in combination with docetaxel or carboplatin and paclitaxel, at doses ranging from 0.05 mg/kg to 20 mg/kg. Eighty patients were enrolled on phase 1 studies of CP-751,871, with 47 (59%) patients having CTCs detected during the study. Prior to treatment 26 patients (33%) had CTCs, with 23 having detectable IGF-1R positive CTCs. CP-751,871 alone, and CP-751,871 with cytotoxic chemotherapy, decreased CTCs and IGF-1R positive CTCs; these increased towards the end of the 21-day cycle in some patients, falling again with retreatment. CTCs were commonest in advanced hormone refractory prostate cancer (11/20). Detectable IGF-1R expression on CTCs before treatment with CP-751,871 and docetaxel was associated with a higher frequency of PSA decline by more than 50% (6/10 vs 2/8 patients). A relationship was observed between sustained falls in CTCs counts and PSA declines by more than 50%. Conclusions: IGF-1R expression is detectable by immunofluorescence on CTCs. These data support the further evaluation of CTCs in pharmacodynamic studies and patient selection, particularly in advanced prostate cancer.

No significant financial relationships to disclose.
Irestatin, a potent inhibitor of IRE1α and the unfolded protein response, is a hypoxia-selective cytotoxin and impairs tumor growth
Authors: Feldman D. , Koong A. C.
Published: March 2020

3514

Background: The unfolded protein response (UPR) is an adaptive response to the toxic accumulation of misfolded proteins in the endoplasmic reticulum (ER), and is activated in solid tumors. IRE1a is a core component of the UPR and responds to ER stress through activation of its dual kinase and endonuclease domains. The IRE1a endonuclease splices the mRNA for XBP-1, generateing a potent transcription factor that is required for tumor growth. Methods: We developed a fibrosarcoma cell line expressing a fusion of unprocessed XBP-1 inserted upstream of firefly luciferase. Under ER stress, IRE1a catalyzes the removal of a 26-nt intronic sequence from the XBP-1 mRNA, introducing a shift in reading frame that permits translation of luciferase. We screened a chemical library of 66,000 small molecules for inhibitors of XBP-luciferase activity and identified 12 molecules, termed irestatins, which consistently inhibited the IRE1a signaling module without affecting the activity of a control CMV-luciferase reporter. We pursued several of the most potent irestatins, including irestatin 9389, which inhibited XBP-luciferase activity with an IC50 of ∼25 nM. Results: Irestatin-mediated inhibition of the IRE1a endonuclease impairs the growth of malignant myeloma cells and inhibits the survival of oxygen-starved tumor cells in vitro. Exposure to irestatin 9389 (2.5 μM) had a negligible effect on the survival of HT1080 cells cultured under normal oxygen conditions. However, in cells cultured under hypoxia for 48 hours, irestatin 9389 inhibited colony formation by nearly 80-fold (48% vs. 0.62%). A two-week course of treatment with single-agent irestatin 9389 (50 mg/kg) administered every other day by i.p. bolus injection was well tolerated and strongly inhibited the growth of subcutaneous HT1080 tumor xenografts (1790 ± 380 mm3 vs. 480 ± 210 mm3; P<0.01). Conclusion: Irestatins define a novel class of hypoxia- and ER stress-selective agents targeted to the underlying physiological response to the tumor microenvironment. Intratumoral inhibition of the UPR can potentiate cell death and impair tumor growth. Molecular intervention against central components of the UPR may represent an effective therapeutic strategy in cancer treatment.

No significant financial relationships to disclose.
Phase I and biomarker study of ABT869, a multiple receptor tyrosine kinase inhibitor, in patients with refractory solid malignancies
Authors: Wong C. I. , Thng C. H. , Soo R. , Chen C. S. , Sukri N. , Gupta N. , McKeegan E. , Lee S. C. , Humerickhouse R. , Goh B. C.
Published: March 2020

3519

Background: ABT869 is an orally administered, potent and specific inhibitor of all VEGF and PDGF family tyrosine kinases, including FLT-3, and c-kit receptors. Methods: A phase I study of ABT869 in patients with refractory solid malignancies was initiated to determine the maximum tolerable dose (MTD) of ABT869 given by continuous once-daily oral dosing; evaluate ABT869 pharmacokinetics; assess pharmacodynamic effects on plasma VEGF and circulating endothelial cells (CECs); evaluate tumor response, including an assessment of microcirculatory parameters DCE-MRI. Dose escalation was planned in dose cohorts of 3 patients each. Treatment periods (TP) were defined as 21 days and tumor assessments were performed using CT scans every 6 weeks. DCE-MRI was done at baseline, day 3 and 14 of the first cycle. Cohort expansion to 6 patients was planned if dose limiting toxicity (DLT) occurred in the first cycle of treatment, and MTD was defined as the dose at which ≥ 2/6 patients experienced DLT. Results: 21 evaluable patients (11 male, 10 female patients median age 58 range 29–76) were treated; 6 at 10mg per day, 12 at 0.25mg/kg/day and 3 at 0.3mg/kg/day. Cycle 1 DLTs included fatigue (grade(G) 3 DLT in 1 patient at 10mg), G3 foot rash, proteinuria and hypertension in 1 patient each at 0.25mg/kg/day (RPTD) and 2 patients with G3 hypertension, including G3 proteinuria in one of these patients, at 0.3mg/kg/day (MTD). Other common treatment-related adverse events at RPTD included asthenia, myalgia, mouth irritation, pneumothorax related to cavitating lung nodule in 2 patients. Pharmacokinetics of ABT869 demonstrated oral clearance of 2.8 ± 1.2 L/h, (mean ± SD, N=16) and half-life of 16.9 ± 5.0 h, with minimal drug accumulation at day 15. 2 PRs were seen in NSCLC patients and stable disease > 4 TPs was observed in 12 patients, with CT scan evidence of cavitation of pulmonary disease and reduced DCE-MRI derived parameters. Mean peak plasma VEGF levels were increased significantly from baseline (p=0.031). CEPs and CECs were reduced in most patients by day 15. Conclusions: 0.25mg/kg/day is the RPTD of ABT869. Modulation of plasma VEGF, CECs and DCE MRI show drug activity consistent with antiangiogenic activity. Promising clinical activity is seen, particularly in NSCLC.

No significant financial relationships to disclose.
Phase I study of AZD0530, an oral potent inhibitor of Src kinase: First demonstration of inhibition of Src activity in human cancers
Authors: Tabernero J. , Cervantes A. , Hoekman K. , Hurwitz H. I. , Jodrell D. I. , Hamberg P. , Stuart M. , Green T. P. , Iacona R. B. , Baselga J.
Published: March 2020

3520

Background: Agents that specifically inhibit the invasive phenotype of cancers are urgently required. AZD0530 is a potent, orally administered inhibitor of Src that has been shown preclinically to prevent phosphorylation of downstream mediators of motility and invasion, paxillin (Pax) and focal adhesion kinase (FAK), with inhibition of metastasis in vivo. Although Src activation is associated with poor prognosis, inhibition of Src activity in human cancers has never been demonstrated. Methods: Patients with cancer received AZD0530 in dose cohorts of 50 mg to 250 mg daily in this 2-part Phase I study. Paired tumor biopsies were acquired for investigation of Src inhibition. Part A defined MTD, toxicity profile and PK. Part B expanded the 50 mg, 125 mg and 175 mg cohorts to characterize changes in phosphorylation of the Src substrates Pax and FAK by evaluating intensity and localization of staining by IHC. Biopsy samples were assigned as pre- or post-AZD0530 treatment by an independent pathology panel blinded to treatment status, and tested for 80% concordance at a 10% alpha. Markers of bone turnover were collected. Results: There were 81 patients evaluable for safety assessment. The median number of prior therapies was 5 (1–27). Part A: DLTs occurred in 3 patients at 250 mg (leukopenia; septic shock (grd5) with renal failure; asthenia) and in 2 patients at 200 mg (febrile neutropenia; dyspnea). Part B confirmed the 50, 125 and 175 mg doses to be tolerable. The mean duration of AZD0530 treatment was 44 days (6–217); 11 patients were treated for longer than 3 months. The pathology panel found consistent modulation of phosphorylation and/or cellular localization of tumor Pax (P=0.067) and FAK (P=0.002) consequent to AZD0530 therapy. There was a dose response trend for reductions in Pax phosphorylation. Bone biomarker and PK data will be presented. Conclusion: For the first time, biomarkers have confirmed inhibition of Src in human cancers. AZD0530 is well tolerated at doses that demonstrate significant inhibition of Src activity. The trend for dose response changes in biomarkers of Src inhibition indicates that the MTD should be taken forward in further development. AZD0530 has a potential role in the prevention of metastases and invasion.

No significant financial relationships to disclose.
First-in-human study of AMG 386, a selective angiopoietin1/2-neutralizing peptibody, in adult patients with advanced solid tumors
Authors: Rosen L. S. , Hong D. , Chap L. , Kurzrock R. , Garcia A. , Rasmussen E. , Nguyen L. , Hwang Y. , Storgard C. , Herbst R. S.
Published: March 2020

3522

Introduction: AMG 386 is a selective angiopoietin1/2-neutralizing peptibody that inhibits angiogenesis by preventing interaction of angiopoietins with Tie2 receptors. This first-in-human study evaluated the safety, pharmacokinetics (PK), and tumor response of AMG 386 in adults with advanced solid tumors. Methods: Patients (pts) in sequential cohorts received weekly IV AMG 386 at 0.3, 1, 3, 10, and 30 mg/kg. Safety assessments were adverse events (AEs), laboratory data, vital signs, ECGs, and anti-AMG 386 antibodies. Tumor response was assessed via RECIST criteria, DCE-MRI, FDG-PET, and volumetric CT. Results: As of Oct. 2, 2006, enrollment is complete with 32 pts (15 men, mean [SD] age 58 [12] years). One dose-limiting toxicity was seen at 30 mg/kg: respiratory arrest likely related to tumor burden, deemed possibly related to AMG 386. Other treatment-related toxicities were all = Grade 2; those observed in = 2 pts were fatigue (n=8), nausea (n=2), and peripheral edema (n=4). PK was dose-linear (mean terminal half-life, 3.1 to 6.3 days). AMG 386 appeared to reach a steady state after 3 doses, with minimal accumulation. Two pts developed binding antibodies to AMG 386; in 1 pt, they disappeared at wk 6. No neutralizing antibodies were seen. Sixteen pts had stable disease (4–52 wks, median 8 wks); 13 had progressive disease; 3 were not evaluable. One pt with ovarian cancer remains active at 52 weeks with 27% tumor shrinkage and investigator-reported reduction in serum CA-125 from 217 U/ml pretreatment to 73 U/ml (wk 4) and 31 U/ml (wk 48). A significant vascular effect (> 20% reduction) was seen by DCE-MRI in 7 of 12 (58%) evaluable subjects. Reduction in SUVmax (FDG-PET) accompanied reduction in IAUC (DCE-MRI) in 5 of 6 evaluable patients. Conclusions: Weekly administration of AMG 386 appeared to be generally well tolerated, with 1 AE > Grade 2 and no reports of the toxicities associated with VEGF blockade (hypertension, proteinuria, bleeding/clotting). Half of pts experienced stable disease; 1 has a sustained minor clinical response accompanied by a biologic response. Further clinical studies of AMG 386 in combination with chemotherapy and other targeted agents are warranted.

No significant financial relationships to disclose.
Phase I study of YM155, a first-in-class survivin suppressant, in patients with advanced solid tumors in Japan
Authors: Nakagawa K. , Satoh T. , Okamoto I. , Miyazaki M. , Morinaga R. , Tsuya A. , Hasegawa Y. , Terashima M. , Ueda S. , Fukuoka M.
Published: March 2020

3536

Background: YM155 is a small molecule expected to induce apoptosis in tumor tissue by suppressing survivin. In the US, a phase I study was conducted with a 168-hr continuous infusion every 3 wks. In Japan, we conducted a similar phase I study to evaluate toxicity profile of YM155 compared with the results of the US study. Methods: The objectives were to determine the MTD, characterize the pharmacokinetics (PK) and observe anti-tumor activity. A standard 3+3 dose escalation scheme was utilized. Results: 34 pts (M/F: 24/10, median age 60, range 26 - 81) were enrolled into 6 dose cohorts [1.8 mg/m2/day (N=3), 3.6 (6), 4.8 (6), 6.0 (8), 8.0 (6), and 10.6 (5)]. 2/5 pts experienced dose-limiting toxicities (DLT) during cycle (C) 1 at 10.6 mg/m2/day (blood creatinine increased (2), lymphocyte count decreased (1)), thus the MTD was 8.0 mg/m2/day. Both pts experienced a DLT (56 yo female, 57 yo male), reached to NCI-CTC grade 2 blood creatinine level at the end of infusion. One of them developed to grade 3 blood creatinine level on day10. They recovered to grade 1 or below in 2 wks without plasma dialysis, so that they continued YM155 infusion decreased to 8.0 mg/m2/day. Renal parameters of them changed in a regular manner, as urine microalbumin increased from day 3 to 7, protein urine from day 6 to 8, and blood creatinine from day 8 to 10. As the other DLT during C1, 1/6 pt experienced AST increased at 6.0 mg/m2/day.. The most frequent AEs were: fatigue (39%), urine microalbumin present (39%), pyrexia (33%), and anemia / haemoglobin decreased (30%). At the MTD, the median YM155 clearance was 39 L/hr with a median steady state concentration of 13 ng/mL and a median terminal half-life of 20 hours. 9/33 pts showed stable disease (SD) and minor tumor shrinkage was observed in 5 of them. One pt (thyroid carcinoma) is ongoing (40 wks) and has had disappearance of pleural effusion. Another patient (malignant fibrous histiocytoma) showed tumor regression in abdominal cavity confirmed by CT scan. Conclusions: YM155, the first survivin suppressant, was well tolerated and the MTD was 8.0 mg/m2/day x 168-hr in Japan. The contribution of YM155 to the treatment of advanced solid tumors should be evaluated in further trials.

No significant financial relationships to disclose.
Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin for targeted therapy of mesothelin expressing mesotheliomas, ovarian and pancreatic cancer
Authors: Hassan R. , Bullock S. , Premkumar A. , Kreitman R. J. , Kindler H. , Willingham M. , Pastan I.
Published: March 2020

3553

Background: Mesothelin, a cell surface glycoprotein, is an attractive candidate for targeted cancer therapy given its limited expression on normal mesothelial cells and high expression in several human cancers including mesothelioma, ovarian and pancreatic cancer. We conducted a phase I study to determine the maximum tolerated dose (MTD), toxicity and pharmacokinetics of SS1P, a recombinant anti-mesothelin immunotoxin. Methods: SS1P given as a 30 minute intravenous infusion was administered to 34 patients (pts) with advanced mesothelioma (n = 19), ovarian (n = 13) and pancreatic (n = 2) cancer. SS1P was administered every other day (QOD) for 6 doses to 17 pts and then QOD for 3 doses to 17 other pts. Results: The initial cohort of 17 pts received SS1P QOD x 6 doses and the MTD was 18 μg/kg/dose. Dose-limiting toxicity (DLT) included grade 3 urticaria (1 pt) and grade 3 vascular leak syndrome (2 pts). To allow further SS1P dose escalation 17 pts were treated on the QOD x 3 schedule and the MTD was 45 μg/kg/dose. The DLT was grade 3 pleuritis and was seen in 2/2 pts treated at a dose of 60 μg/kg and in 1/9 pts treated at a dose of 45 μg/kg. In all cases the pleuritis resolved completely. No grade 4 toxicity was observed. The most common grade 1/2 toxicities included hypoalbuminemia (21 pts), fatigue (17 pts), fever (9 pts) and edema (9 pts). At the MTD of 45 μg/kg the mean Cmax of SS1P was 483 ng/ml and half-life was 466 minutes. Of the 33 evaluable pts treated, 4 had minor response, 18 had stable disease and 11 had progressive disease. Two pts with stable disease had complete resolution of their ascites. A pt with peritoneal mesothelioma had complete resolution of her abdominal ascites, required no further therapy and died of unrelated causes 5 years after SS1P treatment. In the other pt with ovarian cancer there was resolution of abdominal and pelvic ascites that lasted 6 months. Conclusion: SS1P is well tolerated with pleuritis as the DLT at the highest dose level. Anti-tumor activity was noted in a group of heavily pretreated patients. Based on pre-clinical studies that show marked synergy between SS1P and chemotherapy, phase II clinical trials of SS1P in combination with chemotherapy for the treatment of mesothelin expressing cancers will open in 2007.

No significant financial relationships to disclose.
Organic arsenic in patients (pts) with advanced solid tumors: Phase-1 results of zio-101 (s-dimethylarsino-glutathione)
Authors: Camacho L. H. , Hong D. S. , Gutierrez C. , Parker C. A. , Purdom M. A. , Tannir N. M. , Moulder S. , Gale R. P. , Schwartz B. , Kurzrock R.
Published: March 2020

3554

Background: ZIO-101(S-dimethylarsino-glutathione), a novel organic arsenic, is active against multiple cancers in vitro and in animal models. Anti-cancer activity is multifaceted and is mediated by disrupted mitochondrial function, increased reactive oxygen species (ROS) production, modified signal transduction and anti-angiogenesis. Methods: Phase-1 dose finding study to determine maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), and toxicities of ZIO-101 in patients with advanced solid tumors. Results: 34 pts (18 M/16 F) received 78–588 mg/m2/d IV for 5 consecutive days every 4 weeks. Median age was 61 (range, 42–79 y). Median N prior regimens was 3 (1–5). Pts had colorectal (N=17; 12 evaluable), renal (N=4), lung (N=3), melanoma (N=2), pancreas (N=2) and others (N=6). Median N of cycles was 2 (range, 1–12). MTD is 420 mg/m2/d and DLT was transient confusion, and ataxia. Fatigue, nausea and emesis were = grade-2. ZIO-101 was otherwise well-tolerated: There are no hematological toxicities and no QTc- prolongation. Five patients had stable-disease 4–12 mo (colorectal [N=3], renal [N=2],). PK studies at 420 mg/m2/d: tmax = 1 h (SD + 0.9), Cmax = 1.06 μg/L (SD ± 0.07 μg/mL), t1/2 = 17.8 h (SD ± 1.4 h) and AUC0- 8 = 25.9 mg·h/L (SD ± 0.8mg.h/L). 1 pt had complete resolution of a brain metastasis (renal) and 1 patient had a substantial decrease of a liver metastasis (pancreas). Conclusions: ZIO-101 was well tolerated. MTD is 420 mg/m2/d and DLT is transient confusion and ataxia. There was observed clinical benefit in five patients. Expansion cohort is ongoing to further test toxicities and antitumor activity. Phase II studies are ongoing.

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Circulating endothelial cells and progenitor cells in metastatic renal cell cancer: Predictive value during anti-angiogenic therapy?
Authors: Farace F. , Vielh P. , Plantade A. , Amsellem S. , Bouaita L. , Vassal G. , Bidart J. M. , Fizazi K. , Escudier B.
Published: March 2020

3555

Background: Anti-angiogenic therapy has demonstrated efficacy in the treatment of metastatic renal cell carcinoma (MRCC). New surrogate biomarkers are needed to optimize the potential of this novel therapy. Circulating endothelial cell (CEC) and progenitor cell (CEP) measurement has been proposed to monitor anti-angiogenic drug activity and treatment efficiency. Methods: 21 patients (pts) with MRCC were analysed. Among them, 16 were monitored both at baseline and 2 -3 weeks after start of anti-angiogenic treatment (14 pts received sutinimib and 2, nexavar). CECs were measured in one ml erythocyte lysed whole blood by four color flow cytometry (FCM) and identified by a CD45-CD31+CD146+ 7-amino-actinomycin (7AAD)- phenotype. Enumeration of CEC was validated by spiking whole blood with human umbilical vein cells and by immunohistochemical staining of the cell sorted fraction with endothelial markers (Ulex-Europaeus-lectin-1 and Von Willebrand factor). Median CEC value in 20 healthy subjects was 5.5 /ml (range 0–15) wheras this value was 16/ml (range 0–179) in 80 metastatic cancer patients. CEPs were measured by FCM as extremely rare events with a CD45dimCD34+ VEGFR2+7AAD- phenotype. Results: Median MRCC baseline CEC value was 17/ml (range 3 to 101). 16 pts had CEC levels that were two-fold greater than healthy subjects (>10/ml). Preliminary data showed a dramatic drop in CEC levels in patients that responded to therapy. Median baseline CEP value was 0.49% of hematopoietic stem cells (HSC), with ranges from 0.06% to 9% (absolute counts: 10/ml range 1 to 181/ml). Eight patients had CEP values greater than 1% of HSC and all had high tumor burden. Among the 16 pts monitored, all except 2 showed a dramatic increase in CEPs after treatment suggesting that anti-VEGFR2 targeted therapy might induce peripheral accumulation of CEP. Updated data and correlations with prognostic factors and clinical outcome will be presented. Conclusion: During anti-angiogenic therapy, dramatic changes in both CEC and CEP levels were observed. Predictive values of CEC and CEP are currently under evaluation.

No significant financial relationships to disclose.
In vivo perspective study about the effects of weekly low dose administration of zoledronic acid (ZA) on angiogenesis
Authors: Santini D. , Vincenzi B. , Battistoni F. , Galluzzo S. , Rocci L. , Uzzalli F. , Venditti O. , Grilli C. , Dicuonzo G. , Tonini G.
Published: March 2020

3558

Purpose: Recent data have demonstrated in preclinical tumor models an antiangiogenic and antitumor activity of low weekly doses of ZA. As a consequence, the purpose of this study was to confirm these data, evaluating in cancer patients the modifications in angiogenic cytokines levels following repeated weekly low doses of ZA. Experimental Design: 26 consecutive cancer patients with bone metastases treated, for the first time, with four weekly doses of 1 mg of ZA followed by standard doses (4 mg every 28 days) were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) at different time points: just before and after 1, 7, 14, 21, 28, 56 and 84 days following the first disphosphonate infusion. Results: Basal serum VEGF median levels were significantly decreased just after 7 days (-29.7%) (with only one weekly infusion) (P=0.038), This significant decrease of circulating VEGF levels persisted 14(-33.2%), 21 (-39.4%), 28(-31.8%), 56(-33.6%) and 84(-27.9%) days after the first infusion (respectively, P=0.002, P=0.001, P=0.008, P=0.002, P=0.014). Conclusions: This study confirms, for the first time in humans, that weekly low doses of zoledronic acid could have antiangiogenic properties through a significant and long lasting decrease of VEGF serum levels.

No significant financial relationships to disclose.
Phase 1 studies assessing the safety, PK, and VEGF-modulating effects of PTC299, a novel VEGF expression inhibitor
Authors: Hirawat S. , Elfring G. L. , Northcutt V. J. , Paquette-Lamontagne N. , Davis T. , Weetall M. , Babiak J. , Miller L. L.
Published: March 2020

3562

Background: VEGF expression is regulated posttranscriptionally through the 5’- and 3’- untranslated regions (UTRs) of its mRNA. PTC299 is a novel, orally bioavailable, small molecule that acts via the VEGF 5’-UTR to selectively inhibit tumor VEGF production. In multiple preclinical human tumor xenograft models, PTC299 reduces elevated human VEGF levels in tumor and in circulation, decreases tumor microvessel density, and substantially slows tumor growth. With cytotoxic agents or with other antiangiogenics, PTC299 enhances tumor growth delay. Methods: PTC299 safety in animal toxicology studies supported Phase 1 studies in healthy volunteers. The first study was a Phase 1 single-dose (SD) trial. The second study was a Phase 1, multiple-dose (MD) study assessing BID or TID dosing for 7 days. During dose escalations, 8 subjects (4 males, 4 females; 6 PTC299, 2 placebo) per cohort were randomized in a double-blind manner. A fed-fasting crossover was performed in 12 subjects (6 males, 6 females) in the SD study. Subjects underwent clinical observations, laboratory testing, and blood sampling for PK and circulating VEGF. Results: In the SD study, 52 subjects (age range 18–55 years) were enrolled (40 at 5 dose levels and 12 to assess food effects. In the MD study, 32 subjects (age range 31–78 years) were enrolled (24 to BID dosing and 8 to TID dosing). AEs included: headache, dizziness nausea, vomiting, and stomach discomfort (all Grade 1); and diarrhea (Grade 2). No bleeding, clotting, hypertension, or proteinuria occurred. Cmax and AUC increased proportional to dose. There was a ∼40% increase in the Cmax with food, but no change in AUC. Mean PTC299 Cmax and AUC increased by ∼2-fold over 7 days, exceeding target trough plasma concentrations active in xenograft models. A 2-compartment model describes the PK data. Circulating VEGF levels are being assayed. Conclusions: PTC299 is the first drug designed to modulate post-transcriptional control mechanisms to treat human disease. In these initial studies, PTC299 shows safety at plasma exposures associated with preclinical activity and can be taken without regard to food. Final clinical data on dose ranging, safety, PK, and circulating VEGF levels will be presented. Studies of PTC299 in patients with cancer are being initiated.

No significant financial relationships to disclose.