bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical development of namitecan (ST1968), a novel camptothecin derivative with high antitumor activity: Phase I clinical data
Authors: Hess D. , Boehm S. , Delmonte A. , Gallerani E. , Barbieri P. , Pace S. , Carminati P. , Marsoni S. , Coceani N. , Sessa C.
Published: August 2020

2570

Background: Namitecan is a new water-soluble camptothecin analogue which showed high antitumor activity in preclinical models. Aim of this trial was to determine safety, PK profile and activity in adult patients with advanced solid tumors. Methods: The dose escalation started at 2.5 mg i.v. on days 1 and 8 of a 21 day cycle (D1, D8 Q21D) and increased according to 3+3 cohort design depending on the observed toxicity. Dose limiting toxicity (DLT) definitions were: ANC <0.5x109/L for >5 days; PLT ≥ Grade 3 (CTC V3); grade ≥2 liver/renal toxicity not recovered by D22; any non-hematologic toxicity ≥ Grade 3; D8 dose skipping due to toxicity. Maximum tolerated dose (MTD) and recommended dose (RD) were the primary end-points. Blood and urine samples were collected at cycle 1 for PK evaluation. Results: 31 pts (11 endometrial ca., 5 CRC, 5 ovarian ca., 2 NSCLC, 8 other) have been included, with 6 dose levels evaluated (2.5; 5; 10; 15; 17.5 and 20 mg). 17.5 mg was introduced later when 2/7 DLTs at 20 mg were observed (ANC G4>5days, one with D8 skipping). At 17.5mg 2/4 pts experienced DLTs (ANC G4; D8 skipped). Uncomplicated neutropenia and thrombocytopenia were the most relevant G3/4 hematological toxicities. Other toxicities were mild or moderate asthenia, fatigue and alopecia. The MTD was defined at 17.5 mg and the RD was 15 mg. Stable disease ≥ 6 cycles was recorded in 6 pts (2 stable diseases ≥ 10 cycles). PK was linear and data suggest an entero-hepatic recirculation. No metabolites were found in plasma and the product resulted poorly excreted into urine. Conclusions: The MTD and RD of D1, D8 Q21D schedule have been identified. The study will continue with the evaluation of MTD and RD of a single administration per cycle (D1 Q21D), to optimize the schedule of treatment.

[Table: see text]
Final results of a phase I study of TH-302, a hypoxia-activated cytotoxic prodrug (HAP)
Authors: Bendell J. C. , Weiss G. J. , Infante J. R. , Chiorean E. G. , Borad M. , Tibes R. , Jones S. F. , Langmuir V. K. , Kroll S. , Burris H. A.
Published: August 2020

2573

Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM). TH-302 is essentially inactive under normoxia but in severe hypoxia and in the presence of certain reductases, it is reduced and Br-IPM is released. Methods: Eligible patients (pts) had ECOG ≤1, advanced or metastatic solid tumors, evaluable by RECIST, and acceptable hematologic, liver and renal function. A modified accelerated titration design was used. TH-302 was administered intravenously over 30–60 minutes on Day 1, 8 and 15 of a 28-day cycle. CT scans were obtained after every 2 cycles. Detailed pharmacokinetic sampling was performed on Days 1 and 15. The primary objectives of this study were to determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD). Results: Twenty-nine pts enrolled at 3 sites at 9 dose levels from 7.5–670 mg/m2. Median age: 64y. 20 male/9 female. ECOG 0/1: 16/13. Primary tumor: prostate (8), colorectal (8), lung (5) other (8). Two of 5 pts at 670 mg/m2 had DLT: Herpes simplex perianal/rectal ulcers and dehydration due to mucositis. Reversible skin and mucosal adverse events (AE) occurred in 12 of 15 (80%) pts at ≥480 mg/m2 including grade 3 events in 3 pts. The most common TH-302-related AEs were nausea, skin lesions, vomiting and fatigue. Hematologic toxicity was mild and limited: two pts with grade 1 and one pt with grade 2 neutropenia and five pts with grade 1 thrombocytopenia. Five pts had grade 3 and one grade 4 lymphopenia. Four pts have enrolled at an intermediate dose of 575 mg/m2 with no DLT so this is likely the MTD and is well above the predicted biologic effective dose of 100 mg/m2. One pt with SCLC treated at 480 mg/m2 and one with melanoma treated at 670 mg/m2 had unconfirmed partial responses; 12 pts had stable disease (6 continuing after 4 or more cycles), 7 had PD, 4 were unevaluable and 4 are too early to assess. Cmax and AUC for TH-302 and Br-IPM increased linearly with no accumulation at Day 15. Conclusions: Weekly TH-302 has remarkably little hematologic toxicity. Skin and mucosal AEs have developed at the higher dose levels. Skin/mucosa are known to have hypoxic regions. TH-302 is the first HAP to demonstrate tumor responses in Phase I. The MTD is likely 575 mg/m2. Studies in combination with chemotherapy are ongoing.

[Table: see text]
First-in-human study of a novel nucleoside analogue, CP-4126, in patients with advanced solid tumors
Authors: Nilsson B. , Hendlisz A. , Castella M. , Aamdal S. , Dueland S. , Nyakas M. , Evans J. , Venugopal B. , Rasch W. , Awada A.
Published: August 2020

2577

Background: CP-4126 (gemcitabine 5'-elaidic acid ester) is a novel nucleoside analogue with proven preclinical antitumor activity. Unlike gemcitabine, the intracellular uptake of CP-4126 is independent of nucleoside transporters. The aims of this study were to determine the safety, toxicity, MTD and the RD of CP-4126, to describe its pharmacokinetic (PK) characteristics, and to assess its preliminary antitumor activity. Methods: Patients (pts) with refractory solid tumors, performance status ECOG < 2, with adequate haematologic, renal and hepatic function were enrolled in this dose escalation study (1–6 pts per dose level (DL)). CP-4126 was administered on days (d) 1, 8 and 15 every 4 week by a 30 min IV infusion. Start dose was 30 mg/m2/d and the dose was increased by 100% until toxicity > CTCAE grade 2 occurred. Standard DLT definitions were used. Activity was assessed at the end of every 2nd cycle (cy). Plasma and urine PK were determined during d1 (24 hrs) of cy1; plasma at all DLs and urine at DL= 1400 mg/m2/d. Results: 39 pts have been included, (m =24; f =15 ), median age 60 (range 19–78), receiving 96 cycles (range 1–9) of treatment, with 1 pt/DL from 30 to 240 mg/m2/d. The first grade 2 AE (neutropenia) was reported at 480 mg/m2/d. Most frequent toxicities include nausea, vomiting, fatigue and anorexia, the majority of mild severity (grade 1–2). 5 DLTs have been reported; 800 mg/m2/d (1 pt - d8 dose delay >2 weeks due to grade 3 thrombocytopenia and anaemia); 1000 mg/m2/d (1 pt died 48 hrs after treatment start due to acute lung damage); 1400 mg/m2/d (1 pt - fatigue grade 3); 2 pts at 1600 mg/m2/d (grade 3 ALT/AST elevation [1 pt]; 1 pt grade 4 neutropenia and grade 3 fatigue). Stabilisation of disease (≥ 3 months) reported in 5 pts (pancreas, colon and ovarian cancer) lasting between 3.5 to 8 months. One ovarian pt had a 28.3% reduction in tumor mass. CP-4126 was detected in plasma up to 24 hrs post-dosing. AUC for dFdC exposure was significantly higher than reported with gemcitabine at comparable dose levels. Urinary excretion of the main metabolite dFdU during the first 24 hrs was approximately 60% of dose. Conclusions: CP-4126 is well tolerated and accrual is ongoing at 1400 mg/m2/d to establish RD for phase II studies. Updated results including plasma and urine PK will be presented.

[Table: see text]
Phase I clinical results of an APC-targeted hCGβ vaccine (CDX-1307) with TLR agonists
Authors: Morse M. , Chapman R. , Powderly J. , Keler T. , He L. , Ramakrishna V. , Vitale L. , Clay T. , Green J. , Davis T.
Published: August 2020

3006

Background: Effective immunization requires efficient antigen delivery to antigen presenting cells (APCs). Antigens attached to the human antibody B11, targeting mannose receptors on APCs, have been shown to be processed and presented efficiently, and generate robust immune responses when combined with toll-like receptor (TLR) agonists. The CDX-1307 vaccine is composed of B11 fused with hCGβ, a tumor antigen correlated with advanced stage of disease and poor prognosis in a number of common epithelial cancers, but reported at variable rates of expression. Methods: Two phase I studies investigate intradermal (id) vs. systemic (iv) administration of CDX-1307. Patients with advanced epithelial cancers known to frequently express hCGβ receive 4 biweekly vaccinations of CDX-1307, alone or in combination with immunostimulants including GM-CSF (GM), the TLR3 agonist Poly-ICLC, and the TLR7/8 agonist resiquimod. Results: Dose-escalation is complete. In the id study, 37 patients received CDX-1307 at doses of 0.3, 1.0, and 2.5 mg, then 2.5 mg + GM, 2.5 mg + GM + Poly-ICLC, and 2.5 mg + GM + resiquimod. 2.5 mg + GM + Poly-ICLC + resiquimod is planned. In the iv study, 24 patients were treated at 1, 3, 10, and 30 mg, as well as 10 mg + GM and 30 mg + GM. 30 mg + GM + Poly-ICLC is enrolling. Treatment-related toxicities were generally mild to moderate with no dose-limiting toxicities, most frequently injection site reactions and fatigue in the id study, and fatigue, myalgia, and flu-like illness in the iv study. Humoral responses to hCGβ were increased in 56% of the analyzed patients receiving adjuvants. Serum hCGβ was frequently elevated at study entry or during treatment (males = 88%, females = 53%, pancreatic = 89%, colorectal = 78%, breast = 47%). hCGβ decreases were seen in some patients with immune responses. To date, a significant mixed response was seen in one patient with pancreatic cancer (id), while stable disease has been seen in 4 patients (2 with breast cancer = 25, 27 weeks and 2 with colorectal cancer = 9+ weeks). Conclusions: CDX-1307 is well tolerated and results in immune responses that are enhanced by immunostimulants. Elevated hCGβ was detected at a higher than expected frequency in these tumors.

[Table: see text]
A randomized trial of personalized peptide vaccine (PPV) plus low-dose estramustine (EMP) versus full-dose EMP in patients with hormone-refractory prostate cancer
Authors: Noguchi M. , Uemura H. , Kumon H. , Nasu Y. , Hirao Y. , Matsuoka K. , Kakuma T. , Yamada A. , Itoh K.
Published: August 2020

3007

Background: Personalized selection of the right peptides for each patient could be a novel peptide-based immunotherapy for boosting anti-cancer immunity in many patients (pts). This randomized study evaluated the anti-tumor effect and safety of PPV plus a low-dose EMP compared with full dose EMP for patients with hormone-refractory prostate cancer (HRPC). Methods: This was a randomized (1:1), open labeled, cross-over study in pts with HRPC. Pts were randomized to arm A; PPV plus low-dose EMP (280 mg/day) or arm B; full dose EMP (560 mg/day) according to age and PSA levels. In arm A, prevaccination plasma were measured for their IgG levels for each of the 14 or 12 candidate peptides which can induce HLA-A2 or A24-restricted CTL activity against cancer cells followed by biweekly subcutaneous administration of the top four peptides (3mg each) showing the strongest IgG responses. Disease progression (PD) was defined as three consecutive and 125% increase from baseline PSA levels at least two weeks apart or objective PD by RECIST criteria. After PD, pts were treated with the opposite regime. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival and toxicity. The planned sample size was 80. Results: A total of 54 pts from 4 institutions were enrolled between June 2006 and December 2008. The accural into arms A and B was 27 and 27 pts, respectively. The main pts characteristics are (arm A/B): median age 71/69 years, EOCG performance status 0/1 96%/4% and 100%/0%, HLA A2/A24/A2A24 40%/32%/28% and 54%/27%/19%, median PSA 27/25 ng/ml, and metastatic HRPC 96%/85%. All pts were evaluable for their response at the time of interim analysis. The personalized peptide vaccination was well tolerated with no major adverse effects. Increased levels of IgG responses to the vaccinated peptides were observed in 20 of 23 (87%) patients tested. The median PFS time was 246 days in the arm A group and 85 days in the arm B, respectively. The PFS time in the arm A was statistically longer than that in the arm B (log-rank test: p = 0.0007, hazard ratio: 0.27, 95%CI: 0.12 to 0.615). Conclusions: PPV plus low-dose EMP was associated with improvement in PSA-based PFS compared to full-dose EMP alone.

No significant financial relationships to disclose.
Vaccination of renal cell cancer (RCC) patients with modified vaccinia Ankara (MVA) delivering tumor antigen 5T4 administered alone or with interleukin 2 (IL-2) or interferon-alpha (IFN)
Authors: Amato R. , Hernandez-McClain J. , Harrop R. , Cen P. , Doshi G.
Published: August 2020

3026

Background: The attenuated vaccinia virus (MVA) has been engineered to deliver the tumor antigen 5T4 (TroVax). More than 90% 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 either IL-2 or IFN. Methods: Eligibility: Pathologic diagnosis of clear cell or papillary RCC, progressive measurable metastases, any prior therapy, adequate physiological parameters, Karnofsky performance status ≥ 80%, and no active CNS involvement. A regimen of MVA 5T4 alone or in combination with IL-2 or IFN was given. Results: A total of 53 pts received MVA 5T4 alone or in combination with IL-2 or IFN. 13 pts received MVA 5T4 alone, 25 pts received low dose subcutaneous IL-2, and 15 pts received IFN. Clinical responses were assessed by measuring changes in tumor burden via computed tomography or magnetic resonance imaging scan. 5T4-specific cellular and humoral responses were monitored throughout the study. 5T4 was well tolerated with no serious adverse events attributed to vaccination. Of 48 intention-to-treat pts, 43 mounted 5T4-specific antibody responses. 2 pts showed a complete response for > 36 months and 2 other pts had a partial response for > 24 months and 12 months respectively. 20 pts demonstrated disease stabilization for ≥ 3 months. Median progression-free survival and overall survival for all pts was 3.6 months (range 0.8–29.7) and 13.2 months (range 1–38) respectively. A significant relationship was detected between the magnitude of 5T4-specific antibody response and overall survival. Conclusions: 5T4, whether administered alone or in combination, was well tolerated. High frequency of 5T4-specific immune responses and associated enhanced patient survival is encouraging and warrants further investigation.

[Table: see text]
Antitumor activity of PSMA ADC after progression on docetaxel in a mouse xenograft model of human prostate cancer
Authors: Ma D. , Zhang H. , Kennedy B. , Parsons T. , Olson W. C.
Published: August 2020

3030

Background: Currently, there are no approved therapies for castration-resistant metastatic prostate cancer that has progressed following docetaxel therapy. Prostate-specific membrane antigen (PSMA) is an attractive target for antibody-targeted therapy of prostate cancer due to its abundant and restricted expression on the surface of prostate cancer cells. We have developed a novel antibody-drug conjugate (ADC) by linking a fully human PSMA monoclonal antibody to monomethylauristatin E (MMAE), a potent tubulin inhibitor. Here, we describe the use of PSMA ADC in a mouse model to treat xenografted human prostate tumors that have progressed following docetaxel therapy. Methods: Nude mice were implanted subcutaneously with 5 x 106 C4–2 human prostate cancer cells. Animals were first randomized to receive weekly intravenous (IV) doses of either 2 mg/kg docetaxel (n = 50) or vehicle (n = 10). Docetaxel significantly reduced tumor growth (p = 0.025) during the initial phase of the study; however, most of the tumors later progressed. When the tumor volume of an animal in the docetaxel group exceeded 400 mm3, the animal was rerandomized to receive continued docetaxel therapy (n = 18) or weekly IV doses of 6 mg/kg PSMA ADC (n = 18). Treatment effects were assessed by measuring tumor volume and overall survival. When tumor volume was assessed to be ≥2,000 mm3, animals would be sacrificed. Results: At 134 days following tumor implantation, the survival rate was 100% for animals in the PSMA ADC treatment group; 94% of these mice had tumor sizes <100 mm3. In the continued docetaxel treatment group, 14 of 18 animals that were sacrificed when their tumors exceeded 2,000 mm3; the survival rate was 22%. Therefore, PSMA ADC treatment significantly shrank tumors and increased overall survival of animals compared to continued docetaxel treatment (p < 0.0001). Conclusions: PSMA ADC had antitumor activity in mice to xenografted human prostate tumors that had progressed following docetaxel treatment. Treatment with PSMA ADC significantly extended survival in this setting.

[Table: see text]
Peritoneal carcinomatosis immunotherapy with the trifunctional anti-EpCAM x anti-CD3 antibody catumaxomab in patients with colon, gastric, or pancreatic cancer: Long-term results after a 2-year follow-up
Authors: Ströhlein M. , Lordick F. , Rüttinger D. , Schemanski O. , Jaeger M. , Lindhofer H. , Hennig M. , Lahr A. , Heiss M.
Published: August 2020

3033

Background: Peritoneal carcinomatosis (PC) from gastrointestinal (GI) cancer is associated with a poor outcome. The trifunctional antibody catumaxomab may induce remission by redirecting T-lymphocytes and Fcγ-receptor I/III positive accessory cells to tumor cells. The aim of this study was to investigate the treatment of PC with intraperitoneal catumaxomab. Methods: Patients with epithelial cell adhesion molecule (EpCAM)-positive PC from GI cancer were enrolled in a multicenter phase I study and received four sequential intraperitoneal catumaxomab infusions on days 0, 3, 7, and 10 at increasing doses. Results: Twenty-four patients were enrolled. The maximum tolerated dose (MTD) was reached at 10, 20, 50, and 200 μg on days 0, 3, 7, and 10, respectively. The most common drug-related adverse events at the MTD were fever, vomiting, abdominal pain, skin toxicity, and nausea. Eleven of 17 evaluable patients (65%) were progression-free at final examination: one patient had a complete response and three patients had a partial response. EpCAM-positive cells in peritoneal lavage samples decreased in six of 10 evaluable patients. Patient survival was compared in a post hoc matched-pair analysis with PC patients treated with conventional intravenous chemotherapy. Median survival from the time of diagnosis of PC was 502 days in study patients versus 180 days in control patients (log-rank p = .0083). Conclusions: Intraperitoneal treatment with catumaxomab had an acceptable safety profile. Elimination of tumor cells from peritoneal lavage samples, delayed disease progression, and prolonged survival indicate that intraperitoneal catumaxomab is a promising option for the treatment of PC from GI cancer.

[Table: see text]
Effect of CD37 small modular immuno-pharmaceutical (SMIP) on direct apoptosis in chronic lymphocytic leukemia cells via transcriptional up-regulation of the BH3 family member BIM
Authors: Byrd J. C. , Lapalombella R. , Ramanunni A. , Andritsos L. A. , Flynn J. M. , Baum P. , Thompson P. , Muthusamy N.
Published: August 2020

3035

Background: CD37 is a tetraspan transmembrane family protein selectively expressed on normal and transformed B-cells. A novel CD37SMIP was previously demonstrated to mediate superior direct apoptosis and NK-cell mediated killing of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Methods: Given the superior in vitro apoptosis observed with CD37SMIP treatment and early clinical activity observed in highly refractory CLL patients, we hypothesized that a unique mechanism of cell killing was utilized by CD37SMIP. This was pursued in preclinical studies outlined below. Results: Unlike many other agents utilized to treat CLL, death mediated by CD37SMIP does not depend upon caspase activation. Nonetheless, CD37SMIP treatment of CLL cells promotes time-dependent induction of mitochondrial membrane depolarization, mitochondrial translocation of Bax, and up-regulation of Bim protein. CD37SMIP Bim protein induction occurred concomitantly with an increase in BIM mRNA levels. Electrophoretic mobility shift assay using oligonucleotides of the BIM promoter demonstrated increased protein binding activity in nuclear extracts derived from CD37SMIP treated cells and the physical interaction of FoxO3a transcription factor with the FoxO3a responsive element in the BIM promoter was demonstrated using a “protein pull down” assay and confirmed by chromatin immunoprecipitation assays. Furthermore, CD37SMIP treatment significantly increased BIM promoter regulated luciferase reporter expression in B-CLL cells. Consistent with a primary role of Bim up-regulation in mitochondrial membrane destabilization and apoptosis, transfection of CLL cells with BIM siRNA resulted in inhibition of CD37SMIP-induced mitochondrial membrane depolarization and apoptosis. Conclusions: These studies demonstrate CD37SMIP mediated apoptosis in CLL cells occurs via FoxO3a-dependent transcriptional up-regulation of BIM protein. This distinct mechanism of apoptosis utilized by CD37SMIP contrasts it with other agents used for CLL treatment. Additionally, it provides a mechanism for the promising clinical activity of TRU-016 (humanized CD37SMIP) observed to date in refractory CLL patients.

[Table: see text]
Dendritic cell-based vaccination in combination with gemcitabine/S-1 in patients with advanced pancreatic cancer
Authors: Okamoto M. , Yusa S. , Shimamura K. , Ogawa T. , Tomoda T.
Published: August 2020

3037

Background: Pancreatic cancer has a poor prognosis. Tumor-specific cytotoxic T lymphocytes (CTLs) can be activated in vivo by dendritic cell (DC)-based vaccination. However, clinical responses to the immunotherapy with DC vaccination have only been observed in a minority of patients with solid cancer. Combination with other treatment modalities such as chemotherapy may overcome immunoresistance of cancer cells. It has been shown previously that gemcitabine as well as S-1 sensitises human pancreatic carcinoma cells against CTL-mediated lysis. In the current study, the clinical efficacy of the DC vaccine pulsed with the peptide derived from pancreatic cancer-associated antigen in combination with gemcitabine/S-1 has been evaluated in the patients with advanced, inoperable pancreatic cancer. Methods: Thirteen patients with advanced, inoperable pancreatic cancer refractory to standard treatment were entered the study. DCs that were generated from CD14+ monocytes from leukapheresis by 6-day cultivation with granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4 were matured by OK-432, a streptococcal agent, and were pulsed with the pancreatic cancer-associated antigen. These DCs (1 x 107) were intradermally administered 5 times at 14-day intervals concomitantly combined with gemcitabine and/or S-1. Results: Of the 13 patients, complete response (CR) was observed in 2 (15.4%), partial response (PR) in 7 (54.8%), stable disease (SD) in 2 (15.4%), progressive disease (PD) in 2 (15.4%). Response rate was 69.2%. Survival rate, quality of life, and performance status were markedly increased. Severe side effects of more than grade 3 that were assessed in accordance with NCI-Common Toxicity Criteria v.2.0, were not observed. Conclusions: It was strongly suggested that the DC vaccination pulsed with cancer associated-peptid in combination with gemcitabine and/or S-1 was safety and effective in the patients with the inoperable pancreatic cancer refractory to standard treatment.

No significant financial relationships to disclose.
Pharmacodynamic effects of administration of maytansine conjugated anti-CD22 monoclonal antibodies to cynomolgus monkeys
Authors: Fuh F. K. , Fuji R. , Poon K. A. , Manning W. , Berry K. K. , Ramakrishnan V. , Polson A. , Ebens A. , Prabhu S. , Williams M.
Published: August 2020

3051

Antibody-based B-cell specific therapeutic approaches have revolutionized the treatment of non-Hodgkin's lymphomas (NHL) as well as other hematological malignancies. However, a large variability in clinical response has been observed, and the need to develop effective new treatments remains urgent. A promising approach is the use of antibody-drug conjugates (ADCs), cytotoxic drugs covalently linked to antibodies through specialized chemical linkers for the treatment of NHL. CMC-544, an antibody to a B-cell specific glycoprotein CD22 conjugated to the cytotoxin calicheamicin, has shown clinical activity in patients. In addition, antibodies directed to B-cell targets such as rituximab and epratuzumab are in clinical trials for the treatment of NHL and autoimmune disorders. We have generated10F4v3, an anti-CD22 antibody conjugated to the antimitotic agent maytansine (10F4v3-DM1). DM1 disrupts cellular mitosis through inhibition of tubulin polymerization when internalized into cells. The anti-CD22 DM1 conjugate was shown to have significant potency in preclinical efficacy models of NHL. In order to further characterize this antibody-drug conjugate in preclinical studies, we first evaluated the binding characteristics of the 10F4v3 to peripheral blood B-cells from various geographical sources of cynomolgus monkeys. 10F4v3 bound to peripheral blood B-cells from all cynomolgus monkeys of Indonesian and Mauritian origins, but displayed only limited binding to cynomolgus monkeys of Chinese and Cambodian origins. Therefore, further preclinical evaluation of 10F4v3-DM1 was conducted in Indonesian cynomolgus monkeys to examine the safety, pharmacokinetic, and pharmacodynamic effects in monkeys. B-cells and B-cell subsets were depleted in peripheral blood and lymphoid tissue (spleen, bone marrow) at all doses, with no apparent dose-dependent effects or substantial safety limitations. Based on the nonclinical data, 10F4v3-DM1 exhibits an encouraging pharmacodynamic profile for the potential treatment of non-Hodgkin's lymphoma.

[Table: see text]
Phase I study of obatoclax mesylate (GX15–070MS), a bcl-2 antagonist, plus topotecan in relapsed small cell lung carcinoma and other solid tumors
Authors: Brown A. B. , Rudin C. , Rizvi N. , Travis W. , Takebe N. , James L. P. , Subzwari S. , Tyson L. , Markus S. , Krug L. M.
Published: August 2020

3504

Background: Bcl-2 is a rational target in SCLC since it is overexpressed in 60%-90% of tumors and may play a role in resistance of SCLC to chemotherapy. Obatoclax is a small molecule BH3 mimetic that blocks bcl-2 binding to proapoptotic family members. Obatoclax has growth inhibitory effects in several solid tumor cell lines and xenografts, with at least additive effects in combination with topotecan. The primary objective of this study was to evaluate the safety profile and maximum tolerated dose (MTD) of obatoclax plus topotecan in patients with relapsed SCLC and other solid tumors. Methods: We conducted a phase I dose escalation study using a standard “3+3” design. Obatoclax was administered at 14 or 20 mg/m2 over 3 hours on day 1 every 21 days. A subsequent cohort received obatoclax 14mg/m2 on days 1 and 3. Topotecan was given at 1.25 mg/m2 days 1–5. All patients received pegfilgrastim on day 8. Eligible patients were adults with solid tumors appropriate for treatment with topotecan. Patients with neurologically stable, treated brain mets were eligible. Results: 14 patients have been treated including 8 SCLC, 3 extrapulmonary small cell, 1 carcinoid, 1 Merkel cell and 1 melanoma previously treated with 1 or 2 lines of chemotherapy. Nearly all patients experienced neurologic toxicities during the obatoclax infusion which included ataxia, dysarthria, somnolence and/or mood alteration; these typically resolved 1–2 hours after completion of the infusion. The MTD of obatoclax was 20 mg/m2 on day 1 with Dose Limiting Toxicities (DLT) including grade 3 neurotoxicity (2 pts) and febrile neutropenia. Hematologic toxicity included grade 3/4 anemia (6 pts), thrombocytopenia (5 pts) and neutropenia (5 pts). Other toxicities included mild nausea/vomiting, fatigue, pruritus, and constipation. Clinical activity was seen in patients with SCLC including 1 PR and 4 SD out of 7 evaluable. The median TTP for these SCLC patients was 11 weeks. Conclusions: The recommended phase II dose is obatoclax 14 mg/m2 on days 1 and 3 with topotecan 1.25 mg/m2 on days 1–5 in 21 day cycles. A phase II study in second-line SCLC is open. Supported by NCI U01-CA69856.

No significant financial relationships to disclose.
Phase I study of chidamide (CS055/HBI-8000), a novel histone deacetylase inhibitor, in patients with advanced solid tumors and lymphomas
Authors: Dong M. , Ning Z. , Newman M. J. , Xu J. , Dou G. , Cao H. , Shi Y. , Gingras M. A. , Lu X. , Feng F.
Published: August 2020

3529

Background: Chidamide (CS055/HBI-8000) is a new benzamide type of histone deacetylase (HDAC) inhibitor with low nanomolar activity against HDAC1, 2, 3 and 10. This Phase I study evaluated the safety and tolerability of chidamide in patients (pts) with advanced solid tumors and lymphomas. Methods: 31 pts with refractory or relapsed advanced solid tumors (22) and lymphomas (9) were enrolled in this study. Escalating doses of 5, 10, 17.5, 25, 32.5 and 50 mg Chidamide (each with 3 to 7 pts) were administered orally either twice or three times per week for 4 consecutive weeks every 6 weeks. Results: No dose limiting toxicities (DLTs) were identified in the 2 x per week cohorts (22 pts) up to 50 mg; G2 and G3 hematological toxicities (leukopenia/neutropenia and thrombocytopenia) were observed at 50 mg. DLTs were reported as G3 diarrhea or vomiting in 2 pts in the 3 x per week cohort at 50 mg. Common adverse events were G1/G2, fatigue (n = 11), thrombocytopenia (n = 9), anorexia (n = 8), nausea/vomiting (n = 7), leukopenia/neutropenia (n = 6), hypochromia (n = 6), and diarrhea (n = 5). No cystitis, pericarditis, pericardial effusion or prolonged QTc intervals were observed. Single dose PK analysis in pts with 25, 32.5 and 50 mg revealed T1/2 of 16.8–18.3 h, Tmax of 1–2 h in most cases, and a dose-related increase in Cmax and AUC. Multiple dose PK analysis in pts with 32.5 mg 3 x per week suggested drug accumulation with this regimen. Significant induction of histone (H3) acetylation was observed in peripheral white blood cells, which lasted for 2–3 days in most pts after single dosing. 25 pts with total treatment cycles of 49 (range 1–6) were evaluable for efficacy. 4 pts with T-cell lymphomas (4/5 evaluable) and 1 pt with submandibular adenoid cystic carcinoma achieved PR, and 11 pts (2 B-cell lymphomas and 9 solid tumors) experienced SD. Conclusions: Chidamide was well-tolerated in pts with advanced solid tumors and lymphomas in the tested regimens. In addition, the compound exhibited a relatively long half-life, a long-lasting biomarker response and encouraging antitumor activity at well-tolerated doses. The overall phase I results recommend the 2 x per week regimen for phase II studies.

[Table: see text]
A first-in-human phase I trial of PBI-05204 (oleandrin), an inhibitor of Akt, FGF-2, NF-Kb, and p70S6K in advanced solid tumor patients
Authors: Bidyasar S. , Kurzrock R. , Falchook G. S. , Naing A. , Wheler J. J. , Durand J. , Yang P. , Johansen M. J. , Newman R. A. , Khan R. , Hong D.
Published: August 2020

3537

Background: PBI-05204 contains oleandrin, a cardiac glycoside, which inhibits the α-3 subunit Na-K ATPase pump. Over-expression of the α-3 subunit in malignant cells correlates with the tumor proliferation. Oleandrin inhibits FGF- 2 export and activation of NF-Kβ and inhibits phosphorylation of Akt. PBI-05204 also inhibits p70S6K, decreasing mTOR activity. In this ongoing study of PBI-05204, we sought to determine the DLTs, MTD and recommended phase II dose in advanced solid tumors patients (pts) and to characterize its’ pharmacokinetics (PK) and pharmacodynamics (PD). Methods: This was a standard 3+3 phase I design. PBI-05240 was given orally for 21 days of 28 days. Dose was increased by 100% if no related grade 2 adverse event (AE) was observed and increased by 50% if a grade 2 AE occurred. If no other grade 2 AE were observed then subsequent dose escalation was resumed at 100%. In order to determine drug-mediated changes in pAkt, p70S6K, and S6 (mTOR effectors) expression as a surrogate marker of target effect, peripheral blood mononuclear cells (PBMCs) were obtained in addition to PKs. Results: To date 15 pts have received PBI-05204 at 5 dose levels (0.6 mg to 10.2 mg/day), 2 pts are currently active at dose level 5. No DLT has been observed thus far. 10 out of 15 pts (67%) experienced only grade 1 AEs, most common: fatigue and constipation (20%). No significant cardiac toxicities have been observed, only first degree AV block and grade 2 PVC's. Of the 15 evaluable pts, 3 had stable disease for > 4 months, with bladder, colorectal, and fallopian tube cancer pts having an 11, 16, and 10% reduction by RECIST respectively. PKs initially show dose-dependent peak plasma oleandrin concentrations are reached at 2–4 hr following administration with > 50% cleared in 6 hrs. Western blots of PBMCs showed PBI-05204 markedly reduced phosphorylation of Akt, p70S6K, and S6 in a time dependent manner in 4 pts (1 at dose level 2, and 3 and 2 at dose level 5). Reduction of these effectors was observed concomitantly with relatively higher levels of Na, K-ATPase α-3 subunit expression. Conclusions: PBI-05204 is tolerated up to 10.2/mg/day with very little AE's or cardiotoxicity. Initial response evaluation shows activity in diverse tumors with PD analysis suggesting target effect.

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Preliminary activity in adrenocortical tumor (ACC) in phase I dose escalation study of intermittent oral dosing of OSI-906, a small-molecule insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor in patients with advanced solid tumors
Authors: Carden C. P. , Frentzas S. , Langham M. , Casamayor I. , Stephens A. W. , Poondru S. , Wheaton J. , Lippman S. M. , Kaye S. B. , Kim E. S.
Published: August 2020

3544

Background: IGF-1R is overexpressed in various malignancies, and implicated in proliferation, survival, and metastasis. IGF-1R blockade increases apoptosis and reduces tumor growth in preclinical models. OSI-906 is an oral small molecule tyrosine kinase IGR-1R inhibitor. Methods: Patients (pt) with advanced solid tumours were enrolled to determine safety, tolerability, maximum tolerated dose, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity. Results: 26 pt have been treated (14M:12F, median age 61 yrs) at 10, 20, 40, 80, 150, 300, and 450 mg on days (d) 1–3 q14 d. No dose-limiting toxicities have been observed to date. Drug-related toxicities include grade 1 fatigue, nausea, rash, diarrhea, tachycardia, proteinuria, pruritis and peripheral oedema. Linear PK was observed, with median terminal t1/2 3.5 hr; AUC0-∞ 25.8 μg.hr/mL; Cmax 3.20 μg/ml at 450mg. Plasma OSI-906 concentrations above the estimated efficacious concentration (1 μM) were attained at doses > 40mg. Glucose did not increase with rising OSI-906 concentration, but plasma insulin levels showed an upward trend, indicating potential PD effects. PD data on IGFR phosphorylation were analyzed. In total, 11 pt were treated for > 12 weeks (w). Of 3 pt with ACC, 1 pt had a partial response (43% reduction in primary and multiple lung metastases) and remains on treatment after 16 w, 1 pt was treated for 32 w, and 1 pt progressed after 4 w at 40mg. In addition, 1 pt with heavily pretreated NSCLC was treated for 43 w and 1 pt with progressive myxoid chondrosarcoma remains on treatment after 38 w. Conclusions: OSI 906 had minimal toxicity, dose proportional PK at dose levels up to 450mg tested d 1–3 q14 d, with preliminary antitumor activity seen, particularly in ACC. Dose escalation with 5 and 7 d schedules q14 d continues.

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Final results: A dose escalation phase I study of ARQ 197, a selective c-Met inhibitor, in patients with metastatic solid tumors
Authors: Mekhail T. , Rich T. , Rosen L. , Chai F. , Semic-Suka Z. , Savage R. E. , Senzer N.
Published: August 2020

3548

Background: ARQ 197 is a selective, non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell migration, invasion, and proliferation. Methods: This phase I dose escalation study enrolled patients (pts) with metastatic solid tumors to determine the drug's safety profile, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics (PK), and preliminary antitumor activity. Dose escalation followed an accelerated titration design and was modified to the traditional escalation design (3+3 pts) once grade 2 toxicity was observed. ARQ 197 was initially administered orally twice daily (BID) for 2 weeks followed by 1 week off and then modified to evaluate continuous BID dosing based on favorable safety data. Intra-patient dose-escalation was allowed in this study. Additional pts were enrolled and treated at the 360 mg bid continuous dose, which was determined to be the RP2D in another phase I clinical trial. Results: To date, 65 pts (38 male/27 female; median age 61; 9 colon/colorectal, 8 renal cell carcinoma/kidney, 6 ovarian, 6 sarcoma, 5 lung cancer and 31 others) have been treated at 11 dose levels (10 mg bid to 360 mg bid). All treated pts achieved plasma drug concentrations significantly above in vitro IC50 values. The most common drug-related adverse events (AEs) were fatigue (18.5%) and nausea (12.3%). One case each of the following drug-related serious AEs were reported in 4 pts: anemia, leukopenia, neutropenia, thrombocytopenia, dehydration, liver failure, abdominal pain, nausea, and vomiting. Three pts with neuroendocrine, prostate, or testicular cancer achieved a partial response (PR), 32 demonstrated stable disease (SD) and 13 progressed. The 3 PR pts were initially treated at 10, 40 or 90 mg BID respectively. Their doses were escalated to 50, 70, or 120 mg BID respectively after 18 to 33 weeks on treatment. An overall response rate of 6.3% and a disease control rate (CR+PR+SD) of 72.9% were demonstrated among 48 pts who are evaluable for efficacy. Conclusions: ARQ 197 has demonstrated a favorable safety profile up to the dose of 360 mg bid. Preliminary evidence of anti-cancer activity was observed. Final study data on drug safety, PK and efficacy will be presented.

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Hypoxia-inducible factor-1α (HIF-1α) modulation in combination with anti-angiogenic therapy
Authors: Falchook G. S. , Wheler J. J. , Tannir N. M. , Naing A. , Jackson E. , Hong D. , Lawhorn K. N. , Ng C. , Amin H. , Kurzrock R.
Published: August 2020

3555

Background: HIF-1α mediates adaptive responses to hypoxic conditions induced by anti-angiogenic therapy. Bortezomib has demonstrated the ability to inhibit transcriptional activity of HIF-1α. We hypothesized that the addition of bortezomib to bevacizumab would augment response, and we performed this phase I trial to assess safety, MTD, and correlative studies of anti-angiogenic activity. Methods: Patients with advanced malignancy refractory to standard therapy were eligible. Cohorts of 6 patients received bevacizumab and bortezomib on a 3-week cycle, with a stair-step dose escalation design. Pharmacodynamic assessment included plasma VEGF, VEGFR2, 20S proteasome inhibition, DCE-MRI, and tumor expression of HIF-1α, VEGF, VEGFR2, and polymorphisms of VEGF and VEGFR2. Results: 71 patients were treated, and the MTD was identified at the highest dose level (bevacizumab 15 mg/kg, bortezomib 1.3 mg/m2). Two partial responses were observed in patients with renal cell carcinoma (RCC) (Total patients with RCC = 6). Minor responses or stable disease lasting ≥4 months was achieved in 8 patients, including RCC (1), breast (1), leiomyosarcoma (1), nasopharyngeal (2), hepatocellular (1), neuroendocrine (1), lacrimal gland adenocystic carcinoma (1). The most common drug-related toxicities observed included hypertension (36%), fatigue (34%), thrombocytopenia (29%), and myalgia (19%). 22 patients (31%) experienced no drug-related toxicities greater than grade 1. 56 patients (79%) experienced no drug-related toxicities greater than grade 2. One DLT (G5 bleeding) was observed at the MTD. Plasma VEGF levels demonstrated decreases at 1 and 4 hours post-infusion, followed by increases to levels above baseline on days 2, 3, and at the end of cycle 1. DCE-MRI analysis demonstrated decreases in Ktrans on days 2 and 3. Analysis of HIF-1α expression in biopsies is underway. Conclusions: Combination bevacizumab and bortezomib is well-tolerated and has demonstrated clinical activity in patients with previously treated, advanced malignancy. Pharmacodynamic assessment with biomarkers and DCE-MRI suggests that inhibition of angiogenic activity was achieved. Updated clinical and biomarker data will be presented.

No significant financial relationships to disclose.
Safety and efficacy of neratinib (HKI-272) in combination with paclitaxel in patients with solid tumors
Authors: Chow L. , Jiang Z. , Epstein R. , Bondarenko I. , Awada A. , Coughlin C. , Gauthier E. , Zhao Y. , Abbas R. , Hershman D.
Published: August 2020

3557

Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB inhibitor of the tyrosine kinase receptors, erbB-1,-2 and -4. In this phase 1 study, a combination dose of neratinib plus paclitaxel that is tolerable was determined in patients (pts) with solid tumors, and safety and preliminary efficacy were assessed in pts with erbB-2+ metastatic breast cancer. Methods: In this open label, 2-part study, ascending multiple daily oral doses of neratinib (160 mg, 240 mg) were administered in combination with IV paclitaxel 80 mg/m2, if tolerable, or 70 mg/m2 on days 1, 8 and 15. Pts with solid tumors and pts with only metastatic erbB-2+ breast cancer are enrolled in part 1 and 2, respectively. Tumor measurements were made at screening and at every 8 weeks (2 cycles) by modified RECIST criteria. Timed blood samples were collected for neratinib and paclitaxel plasma concentration determination, and PK analyses were performed using a noncompartmental method. Results: Data for 54 pts as of 30 Oct 2008 are presented (median age [range] of 51.5 [20–74] yrs; 91% female; 26 % with prior trastuzumab treatment of median duration [range] 32.5 [10–52] wks; 15% with prior lapatinib treatment). Tumor types in part 1 included breast, endometrial, cervical, colorectal and esophageal cancer. There were no dose-limiting toxicities (DLTs) at the 240 mg neratinib-80 mg/m2 paclitaxel dose, and as standard doses of neratinib and paclitaxel were reached, there was no reason for further escalation. Neratinib-related AEs, any grade in ≥10% of pts included diarrhea (50%), neutropenia (17%), rash (13%), nausea (11%) and vomiting (11%). Neratinib- related AEs, grade ≥3 in ≥2% of pts were diarrhea (20%), neutropenia (9%) and dehydration (4%). Only 2 pts (at the 240 mg neratinib-80 mg/m2 paclitaxel dose) had dose reductions due to diarrhea. In 35 efficacy evaluable pts, 5 had confirmed partial response (PR). Confirmed clinical benefit (PR and prolonged disease stabilization) was seen in 2 pts in part 1, 1 pt with endometrial cancer and 1 pt with cervical cancer. Conclusions: This combination of 240 mg neratinib and 80 mg/m2 paclitaxel was tolerable with a toxicity profile similar to that observed for neratinib, and had promising antitumor activity in pts with solid tumors and erbB-2 + breast cancer.

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Population pharmacokinetic (PK) analysis of ABT-869 in solid tumors and acute myelogenous leukemia (AML) patients
Authors: Gupta N. , Diderichsen P. M. , Steinberg J. , Ricker J. L. , Humerickhouse R. , Awni W. , Pradhan R.
Published: August 2020

3567

Background: ABT-869 is an orally bioavailable, potent and specific inhibitor of all vascular endothelial growth factor and platelet derived growth factor family receptor tyrosine kinases. The objectives of this analysis were to understand the population pharmacokinetics of ABT-869 and explore the effect of several demographic/disease state covariates influencing ABT-869 disposition. Methods: A population PK analysis of 181 patients (pts) enrolled in two phase 1 (multiple types of solid tumors and AML) and three phase 2 monotherapy studies (non-small cell lung cancer, hepatocellular carcinoma [HCC] and renal cell carcinoma) was conducted. Approximately 90% of pts received ABT-869 based on body-weight dosing while the remaining pts had flat dosing. Available plasma concentrations obtained after intensive and sparse pre-dose PK sampling were analyzed by population PK using the non linear mixed effects modeling (NONMEM) approach. Potential covariates including body weight, body surface area (BSA), age, sex, creatinine clearance (CrCL) and disease state (HCC vs. non-HCC pts) were tested. Results: The mean body weight of enrolled pts was 71 kg and 57% were Asian, 36% Caucasian and 7% other races. The ABT-869 plasma concentration time profile was well described by a one-compartment model with first order absorption and elimination process. Oral clearance (CL/F) was not affected by body weight (range 35–177 kg); however, apparent volume of distribution (V/F) increased by 6L per 0.1 mg/m2 increase in BSA. CrCL (39.9–290.3 ml/min) was not a significant covariate on V/F and CL/F suggesting renally impaired pts do not require a different dose/dosing regimen. HCC pts had ∼40% lower CL/F values than pts with other malignancies suggesting a lower dose would be appropriate for HCC (Child Pugh A and B) pts. Conclusions: Population PK analysis showed that ABT-869 PK can be well described by a one-compartment model with first order absorption and elimination. Race and impaired renal function does not appear to alter PK. HCC pts had lower CL/F value therefore a lower dose may be recommended in these patients. Implications of increased V/F with increasing body size and appropriate dosing strategy are undergoing further analysis.

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Phase I clinical and biomarker study of BIBF 1120, an oral multitarget tyrosine kinase inhibitor, in patients with advanced solid tumors (ST): Impact of CD133- and CD117-positive cells on a biomarker of an antiangiogenic inhibitor
Authors: Okamoto I. , Kaneda H. , Satoh T. , Okamoto W. , Terashima M. , Arao T. , Nishio K. , Nakagawa K. , Konishi K. , Kaiser R.
Published: August 2020

3572

Background: BIBF 1120 (Vargatef) is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases, including vascular endothelial growth factor receptors, fibroblast growth factor receptors and platelet-derived growth factor receptors. Methods: BIBF 1120 (150–250 mg) was administered orally twice-daily (bid) to heavily pre-treated solid tumor (ST) patients to determine safety, tolerability, maximum tolerated dose (MTD) and pharmacokinetics (PK). CD133- and/or CD117 (c-kit)-positive cells from CD34+CD45dim peripheral blood cells were evaluated using flow-cytometry on pre-treatment, Day 2, Day 8 and Day 29. Results: Twenty-one patients were treated at doses of 150 mg bid (n=3), 200 mg bid (n=12) and 250 mg bid (n=6). Dose-limiting toxicities (DLTs) of reversible Grade 3/4 elevated liver enzymes occurred in three of 12 patients at 200 mg bid and three of six patients at 250 mg bid; 200 mg bid was declared as the MTD. Best observed responses were stable disease in 16 (76.2%) patients and median progression-free survival was 113 days (95% CI: 77–119 days). PK analysis indicated that Cmax and AUC increased with increased dose within the dose range tested. Flow cytometry analysis revealed that BIBF 1120 treatment significantly increased the percentage of CD133+CD117- cells (p<0.001) on Day 29 compared with pre-treatment, and conversely decreased that of CD133-CD117+ cells (p<0.01). In addition, CD133+CD117+ cells tended to decrease in responders (stable disease) to a greater extent than in non- responders after treatment. Conclusions: BIBF 1120 dosed continuously at 200 mg bid was well tolerated and appeared to provide some clinical benefit. Our biomarker study provides a novel insight into CD133- and CD117-positive cells as a pharmacodynamic biomarker for an antiangiogenic inhibitor.

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