bluuebunny/crossref_metadata_2025 huggingface dataset:
EGFR expresion in liver metastases in patients with colorectal cancer EGFR negative primary tumour and response to systemic chemotherapy
Authors: Petrovic Z. , Tarabar D. , Doder R.
Published: March 2020

20104

Background: To evaluate expresion of EGFR in liver metastases in patients with colorectal carcinoma EGFR immunohistochemistry (IHC) negative primary tumor and to evaluate response to systemic chemotherapy in this group of patients. Methods: A group of 19 patients with IHC negative EGFR in primary tumor with synchronous liver metastasis were analysed. All patients received irinotecan and/or oxaliplatin based chemotherapy regimen in combination with oral fluoropyrimidines - capecitabine. Results: 10 pts. had EGFR IHC positive expresion in liver metastases. EGFR IHC negative liver metastases were present in 9 pts. In patients with EGFR IHC negative liver metastases 2 pts. had PR, 1 pts. had SD and 6 pts. had PD after chemotherapy. In patients with EGFR IHC positive liver metastases 3 pts. had PR, 2 pts. had SD and 5 pts. had PD after chemotherapy. All pts. with PR were underwent to surgery and/or RFA. Pts. with SD and PD received cetuximab with previous systemic chemotherapy. PFS in this group of pts. is 4,1 month. Conclusions: This study is ongoing. At this moment the results do not support routine determination of EGFR status on distant metastatic sites in patients with colorectal carcinoma and for response to chemotherapy.

No significant financial relationships to disclose.
Radiosensitive effect of gemcitabine on nasopharyngeal carcinoma CNE-1 cell line
Authors: Chen Y. , Yu X.
Published: March 2020

20105

Background: To observe the effect and mechanism of gemcitabine-induced radiosensitization on CNE-1 nasopharyngeal carcinoma cell line. Methods: The cell survival curves were obtained with clonogenic assay. The cell cycle phases were measured with flow cytometric analysis. Results: No cytotoxic effect was observed in 0.1 μM and 2 μM gemcitabine alone group. The radiosensitivities were observed in the groups treated with radiation and gemcitabine exposed in different consistencies and times. The SER were 1.35,1.82; 1.55 and 2.16 respectively. The G1 cell cycle phase block was observed in the two consistency groups after exposing to gemcitabine for 24 hours. Dq were rather lower in 2 μM groups especially that exposed for 24 hours. Conclusions: The radiosensitivity was obviously observed in the groups treated with two consistencies of gemcitabine. The effect was more obviously as the consistency and the exposing time increased. The block of cell cycle from G1 to S and the decrease of sublethal damage repair might be contributed to the mechanism.

No significant financial relationships to disclose.
BRCA1 and BRCA2 germline mutations in Sardinian breast cancer families
Authors: Piras G. , Fancello P. , Monne M. , Santona M. , Landriscina G. , Gabbas A.
Published: March 2020

20118

Background: Germline alterations in the BRCA1 and BRCA2 genes highly predispose to breast and ovarian cancer. In families with BRCA1/2 mutations, identification of mutation carriers is clinically rilevant in view of the options for surveillance and prevention. The general aim of the present research is to contribute to the molecular epidemiology of BRCA1/2 genes in the italian region of Sardinia as a prerequisite for a prevention program based on DNA analysis. Methods: Fifty-two of 172 patients diagnosed with primary invasive breast carcinomas (n = 150) or ovarian cancer (n = 18) and 4 male with breast cancer referring to our departments between 2003 and 2005, had a positive family history for breast and/or ovarian cancer and were selected for BRCA1/2 mutation screening by denaturing high-performance liquid chromatography and DNA sequencing. Onehundred DNAs from healthy women originating from the same geographical area were used as population controls. Results: We identified 7 BRCA sequence alterations: 3 were already described polymorphisms while 4 novel BRCA variants were found in 11 out of 52 (21%) probands. The BRCA23951del3insAT is a novel deleterious mutation which leads to protein truncation at codon 1258 and co-occurred with the missense BRCA2S2546P in 6 probands originating from the same village and in none of the controls. Segregation analysis suggested the cis-position of the two mutations. All mutation carriers shared a common disease-associated BRCA2 haplotype indicating the presence of a founder effect. The BRCA2N272I was first observed in our population and was found in 3 unrelated probands and in none of 200 control chromosomes. The missense BRCA1E1352K mutation was present in 3 patients from two unrelated families with breast and ovarian cancer cases in three generations. Conclusions: In the present study, BRCA2 are more recurrent than BRCA1 mutations as reported for the northern part of the island. Our findings provide new epidemiological data that may be useful in defining the prevalence, mutational spectrum and penetrance of BRCA1/2 in the genetically homogeneous population of Sardinia. A comprehensive map of the BRCA mutations may facilitate screening/testing for inherited risk of breast cancer.

No significant financial relationships to disclose.
Different prediction of distant recurrence risk in primary breast cancer patients stratified by ER and ERBB2 status
Authors: Urban P. , Vuaroqueaux V. , Labuhn M. , Delorenzi M. , Wirapati P. , Dieterich H. , Ehret S. , Fürstenberger G. , Morant R. , Eppenberger U. , Eppenberger-Castori S.
Published: March 2020

20120

Background: Molecular profiling recently defined biological characteristics of several long-recognized breast cancer subtypes including ER-positive (luminal subtype), ER-negative/ERBB2-positive (ERBB2 subtype) and ER-negative/ErBB2-negative (basal-like subtype). Each of these particular subtypes has different impact on patient outcome and should be therefore taken in consideration for individual scoring calculations. Methods: The quantitative RNA expression levels of 70 relevant genes were simultaneously determined in fresh frozen samples of 317 primary breast cancer (BC) patients comprehending ER-positive (70%), ER-negative/ERBB2-positive (15%) and ERBB2-negative/ER-negative (15%) and with known follow-up data. Five years distant recurrence scoring systems were calculated by means of Cox-hazard regression models. Results: Two main prognostic scoring systems were developed: one based on genes relative to proliferation representing tumor growth and its velocity, the other based on proteases. A low proliferation score identified 30% of patients at very good prognosis (probability of distant recurrence 12%, CI: 1.5–22%) all belonging to the ER-positive subcategory as compared to cases with higher proliferation (probability of distant recurrence 31%, 32–38%). The probability to develop distant recurrence within 5 years for 30% of ERBB2-positive patients was of only 12% (CI 0–25%) when accompanied by low levels of proteases as compared to the remaining ERBB2-positive patients with a probability of recurrence of 40% (CI 22–54%). Conclusions: ER, ERBB2 and the expression levels of the few identified genes involved in tumor proliferation and invasion can be easily and precisely detected by means of QRT-PCR. This robust method allows fine tuned prognosis and gives predictive information for the treatment of individual breast cancer.

[Table: see text]
Pharmacokinetics of PT523, a novel aminopterin analogue, in patients with solid tumors
Authors: Supko J. G. , He X. , Sao N. , D’Amato F. , Blaszkowsky L. , Clark J. R. , Shapiro G. I. , Bhargava P. , Appleman L. J. , Eder J. P.
Published: March 2020

2052

Background: Nα-(4-Amino-4-deoxypteroyl)-N5-hemiphthaloyl)-L-ornithine (PT523) is a nonpolyglutamatable aminopterin analogue selected for clinical evaluation based upon properties that confer potential therapeutic advantages over classic and nonclassic antifolates. This report describes the pharmacokinetic (PK) behavior of PT523 in cancer patients as determined in the first phase I trial of the drug. Methods: Adult patients with refractory solid tumors received PT523 as a 5 min iv infusion every 7 days for 3 weeks. Plasma samples were obtained at -5, 4, 10, 15, 20, 30, 45 min; 1, 2, 3, 4, 6, 8, 24, and 48 h after starting the first weekly infusion. Urine was collected and pooled from 0–8, 8–24, and 24–48 h. An LC/MS assay was used to measure PT523 in plasma and urine. Interday accuracy and precision were both <15% at the lowest concentrations measured in plasma (0.50 ng/mL) and urine (50 ng/mL). PK parameters were estimated by standard noncompartmental methods. Results: The PK of PT523 was characterized in 24 patients with normal renal and hepatic function, and a median age of 52 years (range, 28 - 77 years). Data was obtained from groups of at least three patients receiving doses of 5, 6.7, 9, 12, and 16 mg/m2. The PT523 concentration in plasma decreased in a polyexponential manner and the terminal log-linear phase was achieved 4–6 h after dosing. In the 7 patients receiving doses of 16 mg/m2, the mean peak drug concentration in plasma (Cmax) was 5,650 ± 300 ng/mL and the median plasma concentration 48 h after dosing was 1.7 ng/mL (range, 1.0 - 23.4 ng/mL). The apparent biological half-life (t1/2,z), total body clearance (CL) and apparent volume of distribution at steady-state (Vss) were all independent of the dose. Mean ± SD values of PK parameters for the entire cohort of 24 patients were: CL, 1.16 ± 0.31 L/h/m2; t1/2,z, 5.3 ± 1.2 h; Vss, 7.7 ± 1.5 L/m2. The mean amount of the dose excreted as unchanged drug in urine over 48 h was 40 ± 15%. Conclusions: PT523 exhibits linear PK with moderate interpatient variability when administered as a 5 min iv infusion at doses of 5 - 16 mg/m2. Renal clearance is a major route of elimination. Association between the CL of PT523 and creatinine clearance should be evaluated in a future study to assess whether dose modification is warranted for patients with diminished renal function.

No significant financial relationships to disclose.
Continuous intravenous infusion (CIVI) topotecan may be safely combined with tipifarnib
Authors: Hills D. , Liebes L. , Muggia F. , Wright J. , Pavlick A. , Buckley M. , Fry D. , Farrell K. , Hochster H.
Published: March 2020

2064

Background: Dose limiting (DL) myelosuppression occurred when topotecan 1.0 mg/m2/d × 5d was combined with tipifarnib (Proc ASCO, 2001, abst 321). We now report on a 3+3 cohort design to determine the safety and pharmacokinetics (PK) of this combination with topotecan given as CIVI in patients (pts) with refractory solid tumors. Methods: Pts were treated with escalating dose levels of topotecan (0.2–0.4 mg/m2/d) given as 21-day infusion in combination with tipifarnib 200 mg PO bid for 21 d every 28 d. Blood was drawn for topotecan PK and intracellular (PBMC) toposisomerase I on d 1 (baseline) and d 5 (tipifarnib omitted d1, cycle 1), and weekly × 8 for ras-farnesylation (membrane bound fraction). Plasma levels of the closed form of topotecan were determined by SPE and HPLC with fluorometric detection. Topoisomerase I in PBMCs was detected by Western blot. Results: 14 patients were accrued at 3 dose levels: topotecan 0.2 mg/m2/d (3 pts), 0.3 mg/m2/d (3), and 0.4 mg/m2/d (8), combined with tipifarnib. Median age was 50 years (33–62). 32 cycles (median 2) were given. Grade 1–3 fatigue, nausea, thrombocytopenia, neutropenia and anemia were common, and at dose level 3, two heavily-pretreated patients had DL myelosuppression. Six others had no significant toxicity over prolonged times. Of nine evaluable for response, a mucinous peritoneal cancer had a minor response for 5 m, an ovarian granulosa cell tumor had a mixed response in lung metastases for 15 m, and a PNET of bone had a minor response for 17 m; six had progression. Mean steady state (± SD) levels of topotecan for dose levels I, II and III were, respectively, 0.48 ± 08 (N = 3), 1.26 ± 0.32 (N = 3) and 1.47 ± 0.1 (N = 5) ng/ml, and were linear with respect to topotecan dose (r = 0.95). By the end of the 21 d infusion, 90% of baseline topoisomerase I signal was depleted in PBMCs. Conclusions: In contrast with bolus topotecan, CIVI topotecan may be combined at known effective doses with tipifarnib. Recommended phase II doses are 0.4 mg/m2/d × 21 days and 200 mg bid daily for those with limited prior therapy. Phase II studies in gynecologic and breast tumors are planned. Supported by UO1- 76642; CA 16087.

[Table: see text]
HGS-ETR1, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: Results of a phase 1 and PK study
Authors: Chow L. Q. , Eckhardt S. G. , Gustafson D. L. , O’Bryant C. , Hariharan S. , Diab S. , Fox N. L. , Corey A. , Padavic K. , Brown M. , Cohen R. B.
Published: March 2020

2515

Background: HGS-ETR1 (mapatumumab) is a fully-human monoclonal antibody agonistic to the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 1 (TRAIL-R1, DR4). Activation of TRAIL-R1 by HGS-ETR1 initiates a caspase cascade leading to apoptosis. HGS-ETR1 in combination with platinum or taxanes results in at least additive activity in preclinical models. Phase 1 and 2 trials have demonstrated that single agent HGS-ETR1 is well tolerated. Methods: This Phase 1 study assesses the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of HGS-ETR1 in combination with standard doses of paclitaxel and carboplatin. Patients received 3, 10 or 20 mg/kg HGS-ETR1 with paclitaxel (200 mg/m2) and carboplatin (AUC 6) every 21 days for up to 6 cycles in the absence of disease progression. Results: Enrollment is complete; 28 patients have received 106 cycles of HGS-ETR1, including 12 patients in each of the 10 mg/kg and 20 mg/kg cohorts. Fourteen of 28 pts received at least 3 cycles (median = 2.5, range 1–12). Dose-limiting toxicity has been neutropenic fever (attributed to chemotherapy) and hypersensitivity (attributed to HGS-ETR1). Other non-dose limiting adverse events at least possibly related to HGS-ETR1 include fatigue, myalgia, transaminitis, anorexia and arthralgia. Preliminary analyses reveal that carboplatin and paclitaxel PK are not affected by HGS-ETR1. Similarly, the PK profile of HGS-ETR1 is not affected by paclitaxel and carboplatin, with plasma HGS-ETR1 concentrations consistent with those observed in the Phase 1 single agent trials. Three patients with NSCLC and 1 with adenocarcinoma of an unknown primary have experienced a confirmed partial response. Conclusions: HGS-ETR1 can be safely administered with carboplatin and paclitaxel. Evaluation of HGS-ETR1 in combination with other chemotherapeutic regimens is warranted.

[Table: see text]
Adoptive immunotherapy plus cryotherapy in murine model of metastatic colon cancer
Authors: Levy M. Y. , Symons H. , Chowdhury W. , Rodriguez R. , Fuchs E.
Published: March 2020

2520

Background: Cryotherapy provides a known local treatment effect for cancer. Additionally, many reports suggest that preservation of tumor antigens in the cryoablation (cryo) treatment site may lead to a systemic immune response that may treat remote tumor. However, the capacity of cryo to induce a regression of metastatic lesions may be limited by tumor-induced alterations of the immune system, including tumor-specific T cell tolerance and suppression. One method of awakening dormant anti-tumor immunity is by treating cancer-bearing animals with cyclophosphamide (Cy), to eliminate suppressor T cells, and allogeneic donor lymphocyte infusion (DLI), to provide an exogenous source of CD4+ T cell help for endogenous, tumor-specific CD8+ T cells. We therefore asked whether Cy ± DLI could augment the anti-tumor effect of cryo in a mouse metastatic colon cancer model. Methods: BALB-C mice were inoculated on d0 with the 106 syngeneic CT-26 SQ to generate local tumor and 105 IV via tail vein injection to generate lung metastases. The SQ tumor was then treated on d14 with either surgical excision or cryo, and mice were treated further with nothing, Cy alone (200 mg/kg IP on d13), or Cy plus CD8+ T cell-depleted DLI from allogeneic donors. At d102, surviving animals were re-challenged with 105 CT-26 cells IV. 5 previously untreated BALB-C controls were injected at the same time with 105 CT-26 IV. Results: Our data demonstrates a survival advantage of mice treated with Cy plus cryo (med. survival 100.5 days) compared to animals treated with Cy + surgery (med. survival 33d; p = .002). Furthermore, a significant (p = .0006) effect of the adoptive immunotherapy was seen with a comparison between the surgery +Cy group (med. survival 33d), and the surgery +Cy/DLI group (med. survival 60d). There are currently 6/18 mice alive at d143 that received cryo + Cy±DLI. In the re-challenge experiment, all control animals died of tumor by d19 with a med. survival of d18. 6/7 re-treated animals remain alive and free of tumor 41d after tumor re-challenge (p = .0041). Conclusions: These results suggest a systemic immune effect on distant metastases may occur after local cryo when cryo is coupled with Cy alone and Cy+DLI. The results from this experiment warrant further characterization of the mechanisms for the anti-tumor effects observed.

No significant financial relationships to disclose.
Radioimmunotherapy (RIT) of refractory or relapsed Hodgkin’s lymphoma with 90Yttrium-labeled antiferritin antibody
Authors: Decaudin D. , Kadouche J. , Levy R. , Belhamiche M. , Arnaud P. , Alberini J. L. , Lokiec F. M. , Pecking A. P.
Published: March 2020

2534

Background: The aims of this study were to evaluate (1) the tumor targeting of 111Indium-labeled rabbit polyclonal antiferritin antibody (Ab) and (2) the therapeutic efficacy of 90Yttrium-labeled antiferritin Ab in relapsed or refractory Hodgkin’s lymphoma (HL) patients (pts). Methods: After obtention of the patients’ consent, the protocol included a first intravenous injection of 2 mg of antiferritin Ab labeled to 111 MBq (3 mCi) of 111Indium followed by immunoscintigraphy at time 24 and 48 hours and, in case of tumor targeting, one or more intravenous injections of 90Yttrium-labeled antiferritin Ab at various activities. Results: Ten patients were included in the study: median age 32 years (range: 18–43 years); sex ratio M/F 9; stages III and IV at the time of RIT 1 and 9 pts, respectively; median number of chemotherapy regimens 3 (range: 2–4); number of autografted pts 8; number of previously irradiated pts 9; response to last chemotherapy: 6 PR and 4 progressions. All immunoscintigraphies showed a tumor targeting by 111Indium-labeled antiferritin Ab. Nine patients were treated, one case died of HL evolution. Five pts received one 90Yttrium-labeled antiferritin Ab injection, three pts 2 injections (0.5, 5 et 14 months after the first one), and one pt 4 injections (3, 9 et 16 months after the first one). Median injected activity was 13 MBq/kg (0.35 mCi/kg)(range: 7–15 MBq). Among the 9 treated pts, 1 CR, 6 PR, 1 stable disease, and 1 tumor progression were observed (ORR 78%). The median duration of responses were 8 months (range: 7–12 months). Toxicity was mainly hematological, with neutropenia and anemia of grades 1 or 2, and thrombopenia of grades 2 and 3; one pt presented a generalized convulsive crisis 24 hours after the therapeutic injection, without etiologic evidence. Conclusion: These results confirmed those that have been reported by Vriesendorp and Quadri and showed that rabbit polyclonal antiferritin Ab targeted HL tumor sites and had an important therapeutic potential in this discrepancy situation. They warranted therefore further multicentric prospective trials.

[Table: see text]
High affinity promotes more effective ADCC by anti-HER2/neu monoclonal antibodies
Authors: Tang Y. , Alpaugh K. , Lou J. , Litwin S. , Shaller C. , Adams G. , Marks J. , Weiner L.
Published: March 2020

2538

Background: Although monoclonal antibodies have emerged as useful cancer therapeutics, the antibody structural features and biologic properties that maximize therapeutic benefit are not fully understood. Antibody-dependent cellular cytotoxicity (ADCC) is believed to be a major mechanism of some anti-cancer antibodies. Herein, we describe the relationship between antibody affinity and the biologic properties of ADCC. Methods: A series of human IgG1 antibodies was created from the anti-HER2/neu C6.5 scFv and its affinity mutants (affinity ranging from 10−7 to 10−11 M). The IgGs were tested for their ability to elicit ADCC using a standard 51Cr-release assay. The ability of these IgGs to inhibit tumor cell proliferation and to induce apoptosis was evaluated using a colorimetric cell proliferation assay and homogeneous caspase assay/Annexin-V-FLUOS assay, respectively. Three tumor cell lines with differing levels of HER2/neu expression were used as target cells, and unactivated human PBMC from healthy donors were the effector cells. Results: There was a clear influence of both intrinsic and functional affinity on ADCC, with higher levels of peak cytotoxicity as apparent affinity approached 10−11 M. Among the antibodies with apparent affinity of 10−11 M, antibodies with higher intrinsic affinities elicited more ADCC. There also was an affinity-dependent increase in cytotoxicity at lower antibody concentrations and lower effector: target ratios. These antibodies elicited more cytotoxicity against tumor cells expressing high levels of HER2/neu than against cells expressing lower amounts of HER2/neu. None of these IgGs inhibited tumor cell proliferation, or induced apoptosis. Conclusions: Additional studies are needed to determine why, at the same functional avidity, ADCC is improved in antibodies with higher intrinsic affinities. These findings justify the examination of high affinity antibodies for ADCC promotion, although the impaired tumor targeting associated with high affinity may be an important confounding factor in the design of unconjugated anti-tumor antibodies. A careful examination of antibody structure: function relationships is required to develop optimized therapeutic unconjugated antibodies.

No significant financial relationships to disclose.
Treatment of malignant pleural effusion with the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3): Results of a phase I/II study
Authors: Sebastian M. , Schuette W. , Schneller F. , Nilius G. , Lodziewski S. , Passlick B. , Hoffken G. , Friccius-Quecke H. , Jaeger M. , Schmittel A.
Published: March 2020

2548

Background: The trifunctional antibody catumaxomab specifically binds EpCAM+ tumor cells, CD3+ T lymphocytes and accessory cells via the Fcγ RI/III. Thus the antibody induces tumor specific cell mediated cytotoxicity in vitro and in vivo. Its intraperitoneal administration has demonstrated safety and led to efficient tumor cell killing and reduction of malignant ascites in ovarian cancer patients (pts.). The present study was conducted to evaluate safety, tolerability and preliminary efficacy of catumaxomab administered intrapleurally (i.pl.) into pts. with EpCAM+ malignant pleural effusion. Methods: This phase I/II trial was a multi-center uncontrolled, dose-escalating study. Pts. (ECOG ≤3) with recurrent malignant pleural effusion containing EpCAM+ tumor cells were included. Three escalating doses from 5–200 μg catumaxomab were administered i.pl. Primary objectives were toxicity and definition of the maximum tolerated dose (MTD). In addition, preliminary data on efficacy (reduction of pleural fluid and tumor cell killing) were generated. Results: 13/24 pts. received 3 infusions as planned. Reasons for early termination of infusions were 3 deteriorations of performance status, 2 exanthemas, 2 dyspnoea, 2 others. The dose regimen of 20–50–100 μg catumaxomab was defined as MTD. Most frequent drug related AEs were symptoms of cytokine release syndrome. 32 SAEs were reported in 18 pts., 4 SAEs were possibly drug related (1 death due to pleural empyema, 1 pneumonia, 1 erythema, 1 increase of liver enzymes). 8/9 deaths were not drug related but due to underlying disease. Induction of human-anti-mouse (HAMA) or human-anti-rat (HARA) antibodies after treatment was found in 8/11 pts. 8/13 fully treated pts. were defined as responders (1 complete, 4 partial, 3 NA) showing reduction of effusion and of drainage necessity. 5/13 were non-responders. A reduction of tumor cells up to log 5 was seen in 10/13 pts. Conclusions: 20–50–100 μg of catumaxomab can safely be administered i. pl. This regimen will further be investigated in a randomized phase II trial comparing catumaxomab to talcum-based pleurodesis.

[Table: see text]
A phase I vaccine trial of a HER-2/neu peptide incorporated into PLG microspheres in patients with advanced stage HER2-expressing cancers
Authors: Salazar L. G. , Murray J. L. , Disis M. L. , Cheever M.
Published: March 2020

2572

Background: Standard methods for immunization with peptides to elicit cytotoxic T lymphocytes (CTL) have not been well defined. Injection of soluble antigens in most standard vaccine formulations induce helper T cell and antibody responses, but generally fail to elicit CTL. Preclinical studies have shown that peptides incorporated into Poly-lactide-co-glycolide (PLG) microspheres are more effective in eliciting CTL than soluble peptides. Additionally, studies in HLA-A2 transgenic mice have shown GM-CSF and monophosphoryl lipid A (MPL-AF) to be effective adjuvants for induction of CTL with PLG peptide. A Phase I vaccine study was conducted to evaluate the safety and immunogenicity of HER2 peptide p369–377 incorporated in PLG microspheres in combination with GM-CSF or MPL-AF as adjuvant in patients with advanced stage HER2 overexpressing cancers. Methods: Twenty-four HLA-A2+ patients with stage III/IV breast, ovarian, or non-small cell lung cancer were enrolled sequentially into 4 treatment arms (6 patients/arm) and received escalating doses of the vaccine (Arms 1 and 2 received 0.5 mg of HER2 peptide; Arms 3 and 4 received 1.5 mg HER2 peptide) with different adjuvants (Arms 1, 2 and 3 received GM-CSF; Arm 4 received MPL-AF) and by different administration routes (Arm 1 received intradermal injection; Arms 2, 3, and 4 received subcutaneous injection). Vaccines were administered every 28 days for a total of 6 immunizations. Toxicity assessments were conducted at baseline, prior to each vaccine and at follow-up. Immunologic responses were evaluated with IFN-γ ELIspot assay. Results: Fourteen subjects completed all 6 vaccinations. 7 patients withdrew from study because of disease progression. No serious or grade 4 toxicity related to vaccine occurred. Eighteen of 24 subjects were evaluable for immunologic responses. 11/18 subjects (61%) developed a p369–377-specific CTL response. Immune responses did not appear to be related to treatment arm. Conclusions: The HER2 p369–377/PLG vaccine plus adjuvant is safe and elicits HER2-specific T cells in patients with HER2 positive cancers.

No significant financial relationships to disclose.
Increased efficacy and toxicity with combination anti-VEGF therapy using sorafenib and bevacizumab
Authors: Azad N. S. , Posadas E. M. , Kwitkowski V. E. , Annunziata C. M. , Barrett T. , Premkumar A. , Kotz H. L. , Sarosy G. A. , Minasian L. M. , Kohn E. C.
Published: March 2020

3004

Background: The multikinase inhibitor, sorafenib (sor), targets raf-kinase and vascular endothelial growth factor receptor 2 (VEGFR2). Bevacizumab (bev) is a monoclonal antibody against VEGF. We theorized that combining the two agents would have synergistic therapeutic effects. Methods: Eligible pts had advanced solid tumors, good end organ function, and PS ≤ 1. A phase I dose-escalation study (cohort 1) used sor 200 mg po BID, and bev 5 mg/kg q2 wks IV (dose level, DL1) or 10 mg/kg (DL2). After DLT was reached, DL4 was added to cohort 1 which tested sor 200 mg po BID on days 1–5 q wk with bev IV 5 mg/kg q 2 wks in an attempt to minimize toxicity. Cohort 2 is an expansion phase at MTD (DL1: sor 200 mg po BID daily with bev IV 5 mg/kg), randomized to start with single drug for 4 wks. Cohort 2 has extensive translational endpoints, including imaging. Results: 34 pts have enrolled, 16 in cohort 1 and 18 in cohort 2. Tumor types include ovarian cancer (13), melanoma (4), and renal cell carcinoma (3). The median age was 58 yrs (30–76); pts received a median of 6.5 (1–15) prior regimens. In cohort 1, 3/16 pts had PR (19%; duration 4, 5+, 12+ mos), all with ovarian cancer, and 11/16 had stable disease (SD; 69%; 3+ - 13+ mos). 10/13 assessable cohort 2 pts had SD (77%; 3+ - 6.5+ mos). The most common DL1 AEs Gr ≥ 2 were hypertension (HTN; 6/6) and hand-foot syndrome (4/6). Other Gr 3 AEs in DL1 were leukopenia and infection (2; 2). DLT was reached at DL2 when 2/6 patients developed Gr 3 proteinuria (4, 5 gm/24 hr) and 3/6 developed uncontrolled Gr 3 HTN. Dose reduction on daily sor (DL1 and DL2) occurred for 11/12 pts at a median of 2 cycles, but is delayed on the intermittent schedule (DL4). In all pts, common Gr 1–2 AEs were elevated AST/ALT (18), rhinorrhea (12), fatigue (10), and anorexia (4). 4 pts developed Gr 2–3 diarrhea and 4 Gr 2–3 nausea/vomiting. Gastrointestinal fistulae occurred in two pts with PR, occurring within 4 wk of initiation of therapy, both in areas of tumor regression. Serial PET and DCE-MRI results and proteomic signal pathway analysis will be reported. Conclusions: The combination of sorafenib and bevacizumab appeared to increase both clinical effect and toxicity at below recognized single agent doses. Sor 200 mg po BID d1–5 qwk and bev of 5 mg/kg q2 wks is suggested for further study, pending further dose escalation.

No significant financial relationships to disclose.
A phase I pharmacokinetic (PK) and molecular pharmacodynamic (PD) study of the combination of two anti-EGFR therapies, the monoclonal antibody (MAb) cetuximab (C) and the tyrosine kinase inhibitor (TKI) gefitinib (G), in patients (pts) with advanced colorectal (CRC), head and neck (HNC) and non-small cell lung cancer (NSCLC)
Authors: Baselga J. , Schöffski P. , Rojo F. , Dumez H. , Ramos F. J. , Macarulla T. , Cajal R. , Kisker O. , Van Oosterom A. , Tabernero J.
Published: March 2020

3006

Background: C and G are two anti-EGFR agents with different mechanisms of action. We had previously shown a synergistic effect combining the two agents in preclinical models (Matar et al, Clin Cancer Res 2004). This study aims to explore safety, PK and PD changes in tumor and skin at different doses of C/G to define the recommended dose (RD) for further development. Methods: pts were treated at the RD of weekly iv C (400 mg/m2 initial dose, 250 mg/m2 weekly) and oral daily G (250 mg/d) as single agents (5 pts each) and in successive cohorts of combined C/G (3–6 pts each): C (320/200) / G (100), C (400/250) / G (100), C (400/250) / G (250), C (320/200) / G (500) & C (400/250) / G (500) (ongoing). Dose escalation depended on dose limiting toxicity (DLT) rate during the first 28 d. Pre- & on-treatment steady-state (14 d) tumor & skin biopsies were obtained and have been evaluated by IHC for total (t) and phospho (p)-EGFR, p-MAPK, p-Akt, proliferation (Ki67), p27 expression and apoptosis by TUNEL. Gene profiling analysis is ongoing. Results: 35 pts have been treated so far: 20 CRC, 13 HNC & 2 NSCLC; median KI 90 % (70–100); median age 60 years (38–80); 24 males, 11 females. DLTs occurred in 3 pts: 1 pt with G alone with reversible ILD; 1 pt with G (250) / C (400/250) with reversible deafness & 1 pt with G (500) / C (320/200) with grade 3 anorexia and nausea. There were 1 CR (HNC) and 5 PRs (CRC) in the C/G cohorts, and 1 PR (CRC) in the C cohort. Overall, 5 out of 9 (56%) pts with CRC treated in the C/G cohorts presented a PR. PD studies show superior inhibition of p-EGFR, p-MAPK and p-Akt, reduction of proliferation and increased apoptosis (all p values <0.05) in the tumors of pts treated with C/G compared with the single agent cohorts. PK evaluation shows no PK interactions with the 2 drugs. Conclusions: This combination of an anti-EGFR MAb (C) and a TKI (G) is feasible at the RD of both agents. Our findings show encouraging clinical activity, especially in CRC, and superior PD signaling inhibition with the combination without any significant PK interaction. Combined anti-EGFR therapy deserves further evaluation.

[Table: see text]
Phase I study of isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 given as three-times weekly oral dose in patients (pts) with advanced solid tumors
Authors: Carducci M. , Siu L. L. , Sullivan R. , Maclean M. , Kalita A. , Chen E. X. , Pili R. , Martell R. E. , Besterman J. , Reid G. K.
Published: March 2020

3007

Background: MGCD0103 is a novel isotype-selective inhibitor of human HDACs. Deacetylation of histones by HDACs is postulated to inactivate tumor suppressor genes leading to neoplastic transformation. Inhibition of these enzymes might restore normal growth control. Methods: A phase I trial of MGCD0103, given as a three-times weekly oral dose 2 out of every 3 weeks, has been performed in pts with advanced solid tumors. Main endpoints are safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) assessments of HDAC activity and histone acetylation status in buffy coat white cells. Results: Five dose levels have been evaluated (mg/m2): 12.5, 20, 27, 36, and 45. As of January, 2006, 28 pts have been enrolled with the following demographics: M:F = 18:10; median age (range) = 60 (29–75); ECOG 0:1:2 = 9:13:1 (n = 23); primary tumor sites: colorectal (8), renal (5), lung (4), others (11); prior chemotherapy, radiotherapy, immunotherapy were given to 22, 12 and 2 pts, respectively (n=23). A total of 62 cycles have been administered, with median = 2 and range=1–7 cycles. MGCD0103 has been well tolerated; most common AEs (23 pts): grade 1–3 fatigue (91% of pts), grade 1–2 nausea and vomiting (70 and 48%), anorexia (26%), constipation (39%). Disease stabilization > 2 cycles has been observed in 3 renal cell cancer pts (4, 6, and 7 cycles) and 1 colorectal cancer pt (4 cycles). Preliminary PK analyses demonstrated intra-pt PK variability, however co-administration of acidic carbonated beverage (protocol amendment) appears to reduce variability without altering average Cmax or AUC (0–24) comparing Day 1 with Day 14. There was little accumulation or decrease in concentrations with extended dosing, and t1/2 was dose-independent at 7.7–11.3 hr. (±0.6–1.6). PD data reveal dose-dependent maximal inhibition of HDAC activity in patients co-administered an acidic beverage. Conclusions: At doses evaluated MGCD0103 appears tolerated and exhibits favourable PK and PD.

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Role of pharmacogenetic studies in early clinical development: Phase I studies with lapatinib
Authors: Zaks T. Z. , Akkari A. , Briley L. , Mosteler M. , Stead A. G. , Koch K. M. , Sampson C. , Ehm M. , Harris E. , Roses A.
Published: March 2020

3029

Background: Rash and diarrhea are a class effect of ERBB1 inhibitors. These events are relatively mild with Lapatinib (a dual ERBB1/ERBB2 kinase inhibitor). Finding a genetic basis for patients who may be predisposed to these adverse events, from the outset of clinical development, may improve the understanding of the mechanisms of these side effects and may have implications for use and dosing. Methods: DNA was isolated from peripheral blood of 107 Caucasian subjects from eight monotherapy phase I studies including 73 healthy volunteers and 34 cancer patients, 100 of whom had associated pharmacokinetic data. 284 single nucleotide polymorphisms (SNPs) from five candidate genes of transporters (ABCB1, ABCG2) and enzymes (CYP 3A4 and 3A5, and 2C19) for which lapatinib is a substrate were genotyped and examined for associations with pharmacokinetic variables (dose-normalized AUC, Cmax, and Tmax) as well as rash (15 cases) and diarrhea (18 cases). Results: Skin rash and diarrhea in this phase I cohort were only mild, (i.e. grade I or II). Statistically significant associations were observed between 34 SNPs in CYP2C19, rash (22 SNPs) and diarrhea (6 SNPs), and between 15 SNPs in ABCB1 and Tmax. Notably, 3/3 subjects (2 healthy volunteers, one patient) homozygous for the CYP2C19*2 allele experienced both mild rash and diarrhea. Extensive linkage disequilibrium was observed among these associated SNPs. Conclusions: Our results suggest that it is possible to determine pharmacogenetic associations with side effect phenotypes during the earliest phase of clinical drug development. These results are currently being validated on a larger cohort of patients from phase II lapatinib clinical trials.

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A phase I trial of AEG35156 (XIAP antisense) administered as a continuous intravenous infusion in patients with advanced tumors
Authors: Ranson M. , Dive C. , Ward T. , Cummings J. , Connolly K. , Evans S. , Robson L. , Durkin J. , Jolivet J. , Jodrell D.
Published: March 2020

3059

Background: The X-linked inhibitor of apoptosis (XIAP) is a potent anti-apoptotic protein. AEG35156 is a synthetic 2nd generation antisense oligonucleotide to human XIAP that enhances cancer cell apoptosis preclinically as a single agent and in combination with chemotherapeutics. Methods: The primary objective was to establish the maximum tolerated dose (MTD) of AEG35156 given as a 7-day continuous infusion every 3 weeks. Other objectives were to determine AEG35156 pharmacokinetics, XIAP inhibition in peripheral blood mononuclear cells and in tumour cells where feasible and document anti-tumour activity. Results: Sixteen adult patients have completed at least one 7-day infusion. Two dose-limiting toxicities (DLT) were observed in five patients treated at 160 mg/m2/day: grade 3 thrombocytopenia for more than 7 days and grade 3 ALT and AST elevation. Seven patients have been treated at 125 mg/m2/day with one DLT of grade 3 transaminase elevation. An approximately 50% decrease in XIAP mRNA was seen in peripheral blood leucocytes three days after the start of infusions at 160mg/m2/day. One patient with small lymphocytic non-Hodgkin’s lymphoma had marked but short lived decreases in peripheral lymphoblasts during AEG35156 administration closely associated with XIAP mRNA knockdown. One patient with breast cancer had an unconfirmed partial response. The trial has now been amended to also determine the MTD of a 3-day continuous infusion every 3 weeks. Three patients have been treated with 3-day infusions at 160mg/m2/day every 3 weeks with no significant toxicities observed and patients are currently being accrued at 213mg/m2/day. Conclusions: AEG35156 can be safely delivered by continuous infusion and preliminary evidence of XIAP mRNA knockdown and antitumour activity has been observed.

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Abcb1, ugt1a1 and oatp-c polymorphisms predict Irinotecan (CPT-11) toxicity
Authors: Rhodes K. E. , Zhang W. , Yang D. Y. , Gordon M. A. , Schultheis A. M. , Nagashima F. , Iqbal S. , Lenz H.
Published: March 2020

3074

Background: Irinotecan (CPT-11), a topoisomerase I inhibitor, is approved for the use of both first- and second-line chemotherapy in metastatic colorectal cancer (CRC) patients. As of yet, only few reliable molecular markers have been identified for predicting CPT-11 toxicity. In this study, we tested specific gene polymorphisms that are known to be involved in the Irinotecan metabolic pathway: the ATP-binding cassette transporter subfamily (ABCB1, ABCG2 and ABCC2), carboxylesterase 1 (CES1), carboxylesterase 2 (CES2), uridine-diphosphoglucuronosyltransferase 1A1 (UGT1A1),hepatic organic anion transport protein (OATP-C) and cytochrome P450 (CYP3A4). Methods: We ran PCR-RFLP assays using genomic DNA from the blood of 54 advanced CRC patients treated with first-line 5FU/LV and CPT-11 at USC between 1999 and 2003. Results: Our cohort was comprised of 31 men (57%) and 23 women (43%) with a median age of 56 years (range: 34–77 years). Participants represented four ethnicities: 29 Caucasian (54%), 12 Asian (22%), 10 Hispanic (19%), and 3 African-American (6%). Three patients (6%) demonstrated complete response (CR), 20 patients (38%) showed partial response (PR), 24 patients (45%) continued with stable disease (SD), and six patients (11%) were found to have progressive disease (PD). One patient was invaluable for response data. Twenty-four patients (46%) experienced Grade 0–2 toxicity, while 29 (54%) experienced Grade 3–4 toxicity. One patient was inevaluable for toxicity data. The median progression-free survival was 10.9 months (95% CI, 7.6 to 12.1 months), and the median overall survival time was 27.9 months (95% CI, 21.3 to 56.6+ months) with median follow up of 30.0 months (range: 11.2 to 59.9 months). We found that the combination of at least one OATP-C 521 wild-type T allele, at least one ABCB1 1236 C allele and at least one UGT1A1*28 variant 7 repeat demonstrated a statistically significant association with Grade 3/4 toxicities (P=0.002, Fisher’s exact test). Conclusion: This is the first study to combine three independent gene polymorphisms within the same metabolic pathway in order to explain common CPT-11 grade 3–4 toxicity.

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Irinotecan pharmacogenetics: The influence of pharmacodynamic genes
Authors: Hoskins J. M. , Baiget M. , Marcuello E. , Altes A. , McLeod H. L.
Published: March 2020

3075

Background: Pharmacogenetic determinants of the disposition of the topoisomerase I (TOP1) poison, irinotecan, appear to predict patient (pt) risk of developing severe toxicity, but do not explain all reported cases of toxicity or tumor response to irinotecan treatment. Proteins encoded by the TOP1, ADPRT, TDP1, CDC45L, NFKB1 and XRCC1 genes abate the cytotoxic action of camptothecins in vitro. Methods: Genetic variation in the drug target, TOP1, and downstream effectors may influence pt outcomes to irinotecan therapy. A retrospective haplotype-association study was undertaken to investigate the hypothesis. The association between common haplotypes of the 6 candidate genes and severe adverse events (Grade 3/4 diarrhea, neutropenia) and tumor response (objective response, overall survival) was examined in 107 advanced colorectal cancer pts treated with irinotecan-based regimens. Haplotype tags (htSNPs) were selected from haplotype cladograms of each gene. Patient DNA was typed for htSNPs using pyrosequencing and haplotype identities estimated using PHASE v.0.9. Results: Genotype frequencies were in Hardy-Weinberg equilibrium. TOP1 IVS4+61 was related to neutropenia incidence (GG<AG<AA, p<0.05) and TDP1 IVS12+79 to objective response (TT<TG<GG, p<0.05). TOP1 IVS4+61 AG+GG survived longer (24.9 months) than AA pts (7.8 months; p<0.005) and ADPRT +852 (A284A) CT+TT pts longer than CCs (p<0.05). More pts with the XRCC1 3/3 diplotype (83%) had an objective response to therapy than pts with other diplotypes (30%, p<0.05). There was a trend towards more ADPRT 2/2s (33%) experiencing severe neutropenia than pts with other diplotypes (13%, p=0.08). No genetic variant influenced diarrhea incidence. Conclusions: This is the first pharmacogenetic investigation of irinotecan pharmacodynamic factors. Our results suggest TOP1 and ADPRT variants may alter a patient’s risk of experiencing neutropenia and TOP1, TDP1, ADPRT and XRCC1 variants may influence tumor response to irinotecan-based therapies.

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A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in a 3 week on 1 week off schedule in patients with advanced solid tumors
Authors: Lewis N. , Marshall J. , Amelsberg A. , Cohen R. B. , Stopfer P. , Hwang J. , Malik S.
Published: March 2020

3091

Background: BIBW 2992 is a highly potent irreversible dual EGFR /HER2 receptor tyrosine kinase inhibitor. This is the first trial performed in the United States with this compound. Methods: Patients with refractory solid tumors (historically known to express EGFR and/or HER2) with normal end-organ function and PS 0–1 were enrolled into a phase I dose-escalation clinical trial. After completion of eligibility and informed consent, BIBW 2992 was administered orally, once daily, for 21 days followed by a 7-day rest. Three patients were accrued in each cohort using a traditional dose escalation 3+3 trial design. After reaching DLT, the MTD dose group was expanded to 18 patients. PK sampling and skin biopsies were performed at baseline and day 21. Tumor biopsies in appropriate patients were obtained pre- and post-treatment in the final cohort to analyze inhibition of the EGFR pathway. Results: Forty-three patients were enrolled. Dose levels ranged from 10 to 65 mg daily. Tumor types included colon (10), breast (8), pancreas and ovarian (4), thyroid and esophageal (3), prostate and NSCLC (2), gastric, cholangiocarcinoma, basal cell, parotid, NPC, HCC, and mesothelioma (1 ). An interim PK analysis showed that BIBW 2992 exposure and peak plasma concentrations increased with increasing dose on day 1 and at steady state. Steady state was reached at day 8. Adverse events were diarrhea, skin rash, pruritus, mucositis, nausea, and vomiting. Doses were escalated to 65 mg/day, with two DLTs noted (skin rash and mucositis). The 40-mg dose was chosen as the recommended phase II dose based on acceptable toxicity when administered chronically. No objective responses have been observed; however, 15 of 35 evaluable patients (43%) experienced stable disease and have been on treatment for > 3 mos. Four patients have continued in an extension study. Two of these patients are still active and one has been taking BIBW 2992 for approximately 1 year. Conclusion: BIBW 2992 is well tolerated at 40 mg per day using a 21-day, 7-day off-treatment schedule. The adverse events observed were typical of receptor tyrosine kinases, including skin rash, pruritis, mucositis and GI disturbance.

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Tumor response to pre-operative chemotherapy (CT) with FOLFOX-4 for resectable colorectal cancer liver metastases (LM). Interim results of EORTC Intergroup randomized phase III study 40983
Authors: Gruenberger T. , Sorbye H. , Debois M. , Bethe U. , Primrose J. , Rougier P. , Jaeck D. , Finch-Jones M. , Van Cutsem E. , Nordlinger B.
Published: March 2020

3500

Background: After resection of LM, 5y survival is 30%, but cancer recurrence is frequent. The benefit of combining surgery and CT has not yet formally been proven. Methods: This study evaluates the value of pre- and postoperative CT in patients with potentially resectable liver metastases from colorectal cancer. Between September 2000 and July 2004, 364 patients were randomized between peri-operative FOLFOX4 (oxaliplatin 85mg/m2 and LV5FU2), 6 cycles before and 6 cycles after surgery (182 patients), and surgery alone (182 patients). The primary endpoint was progression free survival. The purpose of this analysis was to evaluate tumor response to pre-operative treatment and determine if CT induces a tumor size reduction. Results: Baseline characteristics were similar in both arms: median age: 62.5 yrs, prior adjuvant CT: 41.8%, 1 to 3 metastases: 92.3%, T3 or T4: 80.8%. In the CT arm, 97.7% of the patients were documented to have completed pre-operative CT (81.5% received 6 preoperative cycles). 28.9% of the patients who started pre-operative CT required a dose reduction. Of all patients entered in the trial, 88.3% and 94.9% underwent surgery in the CT and surgery arms, respectively. Resection was achieved in 95.6% of the patients operated (84.4% of all patients) in the CT arm, and 89.2% of the patients operated (84.7% of all patients) in the surgery arm. As previously reported, preoperative chemotherapy was safely administered. From imaging data (CT scan), median sum of largest diameters of lesions was 45 mm [Q1-Q3:28.0–70.0] (both arms) before treatment and decreased to 30 mm [Q1-Q3: 15.0–55.0] after CT (median relative difference of 29.7%). At pathological examination, median sum of largest diameters of lesions was 34.5 mm [Q1-Q3:20.0–53.0] in the CT arm and 45 mm [Q1-Q3: 29.0–69.0] in the surgery arm. Conclusions: CT scan measurements were consistent with those performed at pathological examination. Pre-operative CT with 6 cycles of FOLFOX4 resulted in a decrease in diameter of lesions. Since size of metastases at time of surgery is known to have an impact on survival, it is possible that preoperative chemotherapy will improve survival. Survival data should be available at the end of 2006.

No significant financial relationships to disclose.