bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of intravenous dimethane sulfonate (DMS612, NSC 281612) in advanced malignancies.
Authors: Bates Susan Elaine , Balasubramaniam Sanjeeve , Parise Robert A , Bryla Christina , Bonner William , Redon Christophe E. , Nakamura Asako , Wright John Joseph , Piekarz Richard , Jiang Yixing , Eiseman Julie , Chu Edward , Belani Chandra Prakash , Beumer Jan Hendrik , Appleman Leonard Joseph
Published: March 2020

2553

Background: DMS612 is a dimethane sulfonate compound that was identified as preferentially cytotoxic to renal cell carcinoma (RCC) cell lines in a chemical screen of the NCI-60 panel. DMS612 has bifunctional alkylating activity in vitro. Objectives of this first-in-human phase I study included determining the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), PK and PD of DMS612 administered by 10 minute intravenous infusion on day 1, 8 and 15 of a 28 day cycle. Methods: Eligibility criteria included adults with advanced solid malignancies or lymphoma with ECOG performance status 0-2, life expectancy > 3 months and adequate organ and marrow function. Patients were enrolled using a standard “3+3” dose escalation scheme. Plasma PK of DMS612 and metabolites was assessed by LC-MS/MS. DNA damage PD was assessed by γ-H2AX immunofluorescence. Results: 35 subjects were enrolled (22 male, 13 female) with median age 59 years (41-75). Tumor types included colorectal (8), RCC (4), cervix (2), and urothelial (2). Doses administered were 1.5, 3, 5, 7, 9 and 12 mg/m2. The MTD was determined to be 9 mg/m2, with only one DLT of grade 4 thrombocytopenia in 12 subjects enrolled. The maximum administered dose of 12 mg/m2 was considered to be intolerable after 1 of 3 subjects had grade 4 neutropenia and 1 had prolonged grade 3 thrombocytopenia. Prolonged thrombocytopenia in later cycles was observed in other subjects, including one patient naïve to prior cytotoxic chemotherapy. One subject with RCC had a confirmed partial response at 7 mg/m2. DMS612 was rapidly converted into carboxy, chloroethyl and hydroxyethyl analogues and their glucuronides, some of which retained alkylating activity in vitro. Dose-dependent pharmacodynamic evidence of DNA damage induced by DMS612 in vivo was observed by γ-H2AX immunofluorescance in both peripheral blood lymphocytes and plucked scalp hairs. Conclusions: The MTD of DMS12 administered by intravenous infusion on day 1, 8 and 15 of a 28-day cycle was 9 mg/m2. Pre-clinical and clinical observations suggest that further study of DMS612 in RCC is warranted.
Where to look for sentinel node in breast cancer?
Authors: Scharl Anton J. , Düran Andreas ,   Breast Cancer Center Klinikum Bayreuth GmbH
Published: March 2020

2560

Background: It has been observed, that the caudal Axilla on the border to pectoralis muscle is predicive for the sentinel node. The sono-morphology of lymph nodes has been the subject of multiple publications, usually dealing with malignant melanoma. In the context of sentinel lymph node biopsy (SLNB) in breast cancer patients, the following study examines the feasibility of the sonographic differentiation of the Sentinel lymph node (SLN) from neighboring non-SLNs and whether sentinel-ultrasound-needle localization (SUN) is a useful addition or alternative to current methods of “lymphatic mapping”. Methods: During a prospective study performed from 1/2003 to 9/2005 including 404 breast cancer patients (Tis-T4), the SLNB was performed using patent blue+/- 99Tc-Nanocoll. In addition to and independent of this method, the axilla was sonographically examined for “reactive” lymph nodes n=180 pt. (Siemens Elegra 7.5 MHz). The “reactivity” of the nodes was quantified using an index , which allowed the comparison of adjacent nodes. The most “reactive” lymph node in the caudal axilla was identified as the “Ultrasound-Sentinel-Node”(US-SLN) and has been marked with a wire. Results: In 180 patients the SLN was localized using the standard methods as well as (SUN). The was no difference in detection rates of US-SLN and the standard methods in tumor-free nodes(SLN-). However, for patients with axillary metastases (SLN+) SUN provided superior detection rate (99,1%). The false-negative-rate was reduced from 10,7 % to 1,3%. This was attributed to the embolization of lymph vessels afferent to the metastasized (SLN+) node causing a bypass of the “lymphatic mapping” and inhibiting detection. Conclusions: The SUN–Method is comparable to “lymphatic mapping” in tumor free nodes (SLN -). If SLN is metastasized (SLN+) - SUN is superior to the standard methods in sensitivity and specificity (80%) and the false-negative-rate can be reduced. Systematic axilla sonography is an effective method for the SLN-Localisation, and offers an excellent method for quality control during SLNB.
A phase I study of the safety and pharmacodynamic effects of everolimus in combination with lenalidomide in patients with advanced solid malignancies.
Authors: Owonikoko Taofeek Kunle , Harvey R Donald , Kauh John S , Lewis Colleen Margaret , Hossain Mohammed S , Akintayo Adebowale O , Merriewether A. Rene , Chen Zhengjia , Hawk Natalyn Nicole , Saba Nabil F. , Harris Wayne , Shin Dong Moon , El-Rayes Bassel F , Huang Chunzi , Lonial Sagar , Lawson David H. , Khuri Fadlo Raja , Waller Edmund K. , Ramalingam Suresh S.
Published: March 2020

2576

Background: Everolimus (E), an mTOR inhibitor, and Lenalidomide (L) are both potent anti cancer agents with immunomodulatory effects. Preclinical evidence of enhanced cytotoxicity of the combination of an mTOR inhibitor and lenalidomide provided the rationale for this phase I study. Methods: Patients with advanced solid malignancies, ECOG performance status (PS) 0-2 and adequate organ function were eligible. Using standard 3+3 dose escalation schema, patients were treated in cohorts of three with increasing doses of E (5mg, 10mg) and L (10, 15, 20, 25mg) on day 1-28 of a 28-day cycle. Treatment cycles were repeated until disease progression by RECIST criteria or intolerable toxicity. Pharmacodynamic (PD) effects of treatment on circulating B and T lymphocytes subsets were assessed by multiparameter flow cytometry at baseline and after 2 cycles. Results: We enrolled 21 patients (thyroid-5, salivary gland-5, colon-4, sarcoma-2, and others-5); median age-58 (29-74); male-13; ECOG PS of 0, 1, 2 (3/17/1). Salient grade 3/4 toxicities included rash (67%), anemia (19%) and vomiting (5%) without dose limiting toxicities. The median number of completed cycles was 3 (1 - ≥15) and best response in 14 of 18 evaluable patients was stable disease (range 2- ≥14 months); median PFS was 116 days (14- ≥498). The RP2D of E and L was defined as 10mg and 25mg once daily, respectively. PD endpoint analysis after 2 cycles of treatment showed a significant increase in activated cytotoxic T cell subset (CD8+ICOS1+) in patients with salivary or thyroid cancers compared to other tumor types (+2051.0 vs. +394 vs. -1687.4 respectively; p=0.0303) and a trend for an increase in patients with non-progressing tumors (+661.7 vs. -384.1; p=0.0988). Other significant correlations were: Changes in total B-cells (CD3-CD19+) with PFS; NK cells with age (p=0.0211) and activated T cells (CD3+CD69+; CD3+CD62L-; p=0.01) with gender. Conclusions: The combination of E and L is well tolerated at the recommended single agent doses and showed promising efficacy in neuroendocrine and salivary adenoidcystic carcinoma. Modulation of activated T cell subsets (CD8+ICOS1+) correlates with efficacy of these agents.
Vaccine therapy with tumor-specific mutated ras peptides and IL-2, GM-CSF, or both in adult patients with solid tumors.
Authors: Rahma Osama E. , Hamilton Michael , Dakheel Omar , Steinberg Seth M. , Bernstein Sarah , Schlom Jeffrey , Khleif Samir
Published: March 2020

2577

Background: We have shown in previous trials that vaccination with mutant ras peptides corresponding to the tumor mutation is feasible and can induce specific immune responses against the mutant proteins. Immune adjuvants are used to enhance the effect of antigen vaccines. Here, we tested the ras vaccine in combination with Interleukin-2 (IL-2), GM-CSF, or the combination of both in patients with advanced malignancies. Methods: We treated 53 patients with advanced cancers (38 CRC, 11 pancreatic, 3 NSCLC and 1 cholangiocarcinoma) with 5000µg of the corresponding mutant ras peptide given SQ along with IL-2 (Arm A), GM-CSF (Arm B) or both (Arm C). IL-2 was given SQ at 6.0 million IU/m2/day starting day 5, 5 days/week for 2 weeks. GM-CSF was given SQ in a dose of 100 µg/day one day prior to each vaccination for 4 days. Vaccines were repeated every 4 weeks for a maximum of 15 cycles or until disease progression. Results: The median PFS and OS for the full cohort was 3.6, and 16.9, respectively. Median PFS was 3.9, 3.2 and 3.6 months for arm A, B, C, respectively. Median OS was 17.3, 20.8 and 9.1 months, respectively. There was no difference in PFS or OS between the three arms (p= 0.74 and 0.99, respectively). In a subgroup analysis, patients with advanced CRC had a median PFS and OS of 3.5 and 14.2 months, respectively. Most adverse events were grade I-II toxicities and resolved spontaneously. Conclusions: Two important conclusions came out of this trial: 1) no difference was found in clinical response between the three arms; and 2) although patients with CRC in the subgroup analysis progressed earlier compared to historical control (3.5 vs. 7.3 months), the time from progression to death “post progression survival, PPS” was notably longer (10.3 vs. 5.6 months). This provides further evidence to the emerging understanding of the difference in clinical trial monitoring between immunotherapy and other types of therapy. Accordingly, removing patients with standard CTEP definition of progressive disease may adversely affect the clinical outcome of vaccine therapy. We believe that future clinical trial design strategies in cancer vaccine should be modified to allow patients to continue therapy despite of disease progression.
Effect of the vaccine Ad5 [E1-, E2b-]-CEA(6D) on CEA-directed CMI responses in patients with advanced CEA-expressing malignancies in a phase I/II clinical trial.
Authors: Morse Michael , Hobeika Amy , Chaudhry Arvind , Amalfitano Andrea , Niedzwiecki Donna , Clay Timothy M. , Osada Takuya , Devi Gayathri , Burnett Bruce K. , Weinhold Kent , Hsu Shiaowen David , Blobe Gerard C. , Xu Younong , Nguyen Susan , Dua Rajesh , Balcaitis Stephanie , Gabitzsch Elizabeth , Balint Joseph , Jones Frank , Lyerly H. Kim
Published: March 2020

2585

Background: Adenovirus (Ad) vectors are promising platforms for use as cancer vaccines because of their substantial immunogenicity; however, Ad-specific neutralizing antibodies, present due to natural infection, limit their use. We created a new vector containing additional deletions of the E2b gene and observed that this Ad5 [E1-, E2b-] vector, engineered to express carcinoembryonic antigen (CEA(6D)), could induce antitumor immune responses in mice despite pre-existing Ad5 immunity. The purpose of the current translational study was to evaluate the immunologic effect of increasing doses of Ad5 [E1-, E2b-]-CEA(6D) in mice and then to extended these pre-clinical observations into a phase I/II study. Methods: Ad5 naïve female C57Bl/6 mice, 4-6 weeks old, were immunized subcutaneously 3 times at 2 week intervals with doses of 1.4X107 viral particles (vp) up to1.4X109 vp of Ad5 [E1-, E2b-]-CEA(6D). Two weeks after the last immunization, splenocytes were harvested for immune determinations. Cohorts of patients (n=25 total) with advanced colorectal cancer, refractory to prior therapies, received escalating doses of Ad5 [E1-, E2B-]-CEA(6D) (109 to 1011 vp) subcutaneously every 3 weeks for 3 immunizations.CEA-specific cell mediated immunity was measured by ELISPOT. Results: Increasing doses of Ad5 [E1-, E2b-]-CEA(6D) in mice induced increasing CEA-specifc CMI responses. Similarly, patients who received the highest dose of Ad5 [E1-, E2b-]-CEA(6D) exhibited the highest levels of CEA-specific CMI responses. The induction of CEA-specific CMI responses increased over the course of the 3 injections despite the presence of pre-existing Ad5 immunity in the majority (75%) of patients. There were no drug related grade 3/4 toxicities.Two patients with stable disease remained so during the study. All other patients experienced progressive disease; however, 1-year survival was 54%. Conclusions: Multiple homologous doses of Ad5 [E1-, E2b-]-CEA(6D) could break tolerance and generate CEA-specific CMI responses in the setting of Ad specific immunity in colorectal cancer patients.
Effect of modulation of the hostile tumor microenvironment through adoptive transfer of IL-12 expressing MUC-16 targeted T cells on ovarian tumors in vivo.
Authors: Chekmasova Alena A. , Sandadi Samith , Spriggs David R. , Brentjens Renier J.
Published: March 2020

2586

Background: T cells may be genetically modified to recognize tumor associated antigens (TAAs) through the introduction of genes encoding artificial T cell receptors termed chimeric antigen receptors (CARs). MUC16 (CA125) is an antigen over-expressed on ovarian carcinomas and a serum marker for the diagnosis of ovarian cancer. We have previously demonstrated enhanced antitumor efficacy of CAR+ T cells further modified to secrete IL-12. We therefore tested whether MUC-16 targeted T cells further modified to express IL-12 would exhibit an enhanced antitumor efficacy in a syngeneic immunocompetent tumor model of ovarian cancer. Methods: We have constructed SFG retroviral vectors encoding the second (4H11m28mz) generation CARs as well as IL-12 modified CAR (4H11m28mz/mIL12) targeted to the retained extra-cellular domain of MUC16, termed MUC-CD. We demonstrated an antitumor efficacy of these T cells in a syngeneic tumor model using the C57BL6 (B6) mice intraperitoneally (i.p.) injected with ID8(MUC-CD) tumor cells. Results: In our studies treatment of mice bearing established ID8(MUC-CD) ovarian tumor with MUC-CD specific T cells expressing IL-12 gene, in contrast to T cells targeted to MUC-CD alone, fully eradicate highly advanced intraperitoneal ovarian tumors. Significantly, we found that mice treated with 4H11m28mz/mIL12 T cells had increased number of modified T cells in the peritoneum at day 4 and 7 with increased recruitment of endogenous T cells to the site of the tumor when compared to controls and mice treated with 4H11m28mz T cells. The observed antitumor effect did not required prior lymphodepletion and was well tolerated in treated mice. Conclusions: CAR modified T cells targeted to the MUC-16 antigen efficiently eradicate orthotopic ovarian cancer in syngeneic immunocompetent mice with markedly enhanced antitumor efficacy seen in those mice treated with CAR+ T cells further modified to secrete IL-12. These data support future clinical trials utilizing adoptive T cell therapy in patients with relapsed ovarian cancer.
Clinical pharmacologic considerations for the phase II/III dose/regimen of the investigational Aurora A kinase (AAK) inhibitor MLN8237 (alisertib): Pharmacokinetics (PK), pharmacodynamics (PD), and exposure-safety relationships.
Authors: Venkatakrishnan Karthik , Zhou Xiaofei , Ecsedy Jeffrey , Danaee Hadi , Xiao Hugh , Shi Hongliang , Mould Diane R. , Fingert Howard , Benaim Ely , Kleinfield Robert , Milton Ashley
Published: March 2020

2597

Background: MLN8237, an oral selective AAK inhibitor, is primarily metabolized by multiple glucuronidation enzymes including the polymorphic UGT1A1. Phase 1 studies included comprehensive PK and PD sampling. We report integrated PK, PD, and PK-safety analyses in support of dose/regimen selection for phase 2/3 studies. Methods: Phase 1 studies in adults with advanced cancers evaluated dosing on d 1-7 in 21-d cycles or d 1-21 in 35-d cycles. Data from 294 patients in 4 phase 1 and 2 phase 2 studies contributed to population PK modeling. PD endpoints included mitotic index (MI) in skin and chromosome alignment and spindle bipolarity (CA/SB) in mitotic tumor cells. Logistic regression analyses evaluated relationships between MLN8237 PK parameters and DLTs (N=86) or CNS adverse events (AEs; n=134) in 2 phase 1 studies. Results: MLN8237 displayed dose-linear PK (5-200 mg/d), described by a 2-compartment model with first order absorption. Covariate analyses did not reveal significant effects of age, body size, sex, UGT1A1 genotype, or creatinine clearance (≥30 mL/min). Exposure-related increases in skin MI and decreases in CA/SB in tumor mitotic cells confirmed AAK inhibition by MLN8237. At the MTD of 50 mg BID (d 1-7 dosing) geometric mean steady-state exposures (48,200 nM.hr) were comparable to those associated with ≥50% CA/SB reductions in mitotic tumor cells (57,300 nM.hr). Exposures at the 21-d MTD (QD dosing) were lower, favoring 50 mg BID (d 1-7 dosing) for further development. At 50 mg BID (d 1-7 dosing) logistic regression relating MLN8237 AUC to DLT rate estimated a DLT probability of 8% (95% CI 3-20%). Similar analyses identified Cmax rather than AUC as the predictor of CNS AEs, supporting BID dosing in adults to reduce peak concentrations while preserving total systemic exposure. Conclusions: MLN8237 exhibits dose-linear PK independent of age, body size, mild or moderate renal impairment, or UGT1A1*28 polymorphism. Exposures achieved at or near 50 mg BID are expected to result in tumor AAK inhibition, supporting a pharmacologically active dose range for future clinical development.
Antibody-dependent cell-mediated cytotoxicity (ADCC) evolution under treatment by cetuximab and links with treatment outcome in colorectal cancer (CRC) patients.
Authors: Merlano Marco Carlo , Monteverde Martino , Strola Giuliana , Barriere Jerome , Etienne-Grimaldi Marie-Christine , Miraglio Emanuela , Lattanzio Laura , Vivenza Daniela , Messa Francesca , Lo Nigro Cristiana , Milano Gerard A.
Published: March 2020

2600

Background: ADCC plays a role in antitumor activity of IgG1 mAb by inducing immune cell-mediated lysis of tumor cells. We evaluated ADCC ability before and under cetuximab-based treatment and examined its impact on treatment outcome. Methods: 29 patients (17 men, 12 women, median age 72, range 51-84) with metastatic wild-type KRAS CRC treated with chemotherapy (irinotecan or Folfiri) plus cetuximab were prospectively enrolled. ADCC ex-vivo was measured before starting treatment and every 2 months during treatment (1 to 7 measurements/patient, 12 patients with >2 measurements). 400 000 purified Natural Killer cells (CD3- CD56+) from patients were incubated with 10 000 target cells (CAL166 cancer cell line expressing EGFR) and 10 µg/ml cetuximab (triplicates). Cytotoxicity was measured by the LDH-release assay. ADCC was expressed as the % of lyzed target cells. Gene polymorphisms of Fcγ receptors FCGR2a (131Arg>His) and FCGR3a (158Phe>Val) were analyzed (Allelic Discrimination assay). Results: The feasibility rate of ADCC measurement was 88%. ADCC basal values ranged between 30% and 100% (mean 62%, median 66%). Basal ADCC was not influenced by patient gender. A tendency for an increased ADCC basal value was observed in younger patients: median was 76% in the 6 patients ≤ 60 vs 56% in the 23 patients over 60 years-old (p = 0.031). FCGR2A and FCGR3A gene polymorphisms were not linked to basal ADCC. The evolution of individual ADCC ability before treatment and 2 months later revealed a significant drop in ADCC following treatment initiation (intra-patient comparison, n=18, p=0.006), with an absolute median drop of 19%. This decrease was not sustained over time and intra-patient comparison between basal value and 4-month measurement was not significant. 25 patients were assessable for survival (11 deaths). Basal ADCC values were not related to survival. Conclusions: A new generation of mAb is currently being developed with the aim to amplify ADCC. Present data illustrate the feasibility of ADCC measurement in mAb-treated patients and reveal an initial drop in ADCC under treatment that may reflect the variable chemotherapy-induced impact on host immunity.
Dovitinib (TKI258): Exploration of pharmacokinetics and pharmacodynamics (PK/PD) for dose and regimen consideration.
Authors: Garonzik Samira Merali , Nedelman Jerry , Tan Eugene , Chiparus Ovidiu , Dugan Margaret Han
Published: March 2020

2603

Background: Dovitinib is a potent oral inhibitor of Receptor Tyrosine Kinases with activity against FGFR, VEGFR and PDGFR. The objectives of this analysis are to describe the PK/PD of dovitinib to characterize the differences between two different dosing regimens, 400 mg once daily (qd) or 500 mg 5 days on, 2 days off (int) in terms of exposure and biomarker response. Methods: PK/PD data from 127 patients receiving dovitinib, 100-600 mg int and 50 – 600 mg qd were available. Duration of therapy was 15 to 859 days. Plasma concentration-time data + sparse biomarker (BM) data were available after the first dose and at steady state (SS). Data was analyzed using non-linear mixed effects modeling to characterize nonlinearities in PK as well as BM response. VEGF, sVEGFR2 and PDGF were described by indirect response models and FGF23 was described using a mechanism based model to characterize acute drop, rebound, tolerance and increase to a new SS over time. Results: Raw data revealed prolonged absorption, linear clearance after the first dose, but dose dependent ↓ in clearance at SS (leading to over-proportional accumulation), and apparent linear clearance at doses below 400 mg qd. ↓ exposure for doses up to 400 mg at SS compared to 1st dose implied auto-induction. The PK was well described by a 1-compartment (CMT) model with 3 transit CMTs to characterize absorption lag. Auto-induction and over-proportional accumulation at SS were modeled as depending on cumulative exposure through a time-dependent process with half-life of 18 h. In our study, median (10th – 90th percentile) Clearance was 30 (17 – 80) L/h on Day 1, and 96 (51 – 185) L/h at SS. The model predicted 36%↑in VEGF, 18% ↓ in sVEGFR2, 82% and 57% ↑in PDGF and FGF23 respectively at SS, for median exposure at a dose of 400 mg qd. Simulations of PK and biomarker responses were performed for different dosing regiments to assess relative safety and target effects. Conclusions: The PK/PD model suggests 400 mg qd may lead to over-proportional accumulation of dovitinib in <5% of subjects while int dosing minimizes this. 500 mg int may be a more tolerable regimen while maintaining adequate PD response, and is being used in the pivotal phase III study for dovitinib in patients with mRCC.
Vectorized gene therapy of liver tumors: Safety and proof of concept of TG4023 (MVA-FCU1)/5-FC combination.
Authors: Husseini Faress , Delord Jean-Pierre , Fournel-Frederico Cécile , Kurtz Jean-Emmanuel , Erbs Philippe , Homerin Michel , Halluard Céline , Jemming Chloé , Orange Clélia , Limacher Jean-Marc
Published: March 2020

2605

Background: TG4023 is a non-integrative and non-propagative Modified Vaccinia virus Ankara (MVA) expressing a chimeric yeast transgene (FCU1) coding for cytosine deaminase and uracil phosphoribosyl transferase that transform the pro-drug 5-flucytosine (5-FC) respectively into 5-FU and 5-FUMP in infected cells; these derivatives then diffuse and kill additional tumor cells (bystander effect). Methods: This phase I study determined safety and Maximal Tolerated Dose (MTD) of a single intra-tumor injection of TG4023 combined with a 2-week dosing period of 5-FC 200 mg/kg/day. Plasma and tumor 5-FC (PK) and 5-FU (PD) concentrations were measured. Other assessments were tumor response, changes in tumor markers and immune response. Patient requirements were ≥ 1 injectable primary or metastatic unresectable liver tumor of 2-5 cm, no treatment option left, ECOG PS ≤ 2. Consenting patients were allocated to cohorts according to a 3+3 dose-escalating design driven by Dose-Limiting Toxicities (DLTs) and Data Safety Monitoring Board recommendations. Results: Among 16 enrolled patients (13 colorectal, 1 pancreatic and 1 liver cancers, 1 cancer of unknown primary) 6 were injected in one tumor with 107 plaque forming units (pfu) TG4023, 3 with 108 pfu and 7 with 4.108 pfu, using a multiport needle and ultrasound imaging guidance. 5-FC was given IV the first days then orally. One DLT (grade 3 transient increase in AST/ALT) was recorded at 4.108 pfu; other severe adverse events, diarrhea, hypertension, alkaline phosphatase increase were related to 5-FC; most frequent AEs were transient fever, asthenia, site injection pain, nausea/vomiting. 5-FU concentrations in tumor biopsies at Day 8 were 56±30 ng/g and 1.9± 2.6 ng/mL in plasma. 11/16 injected, 12/23 non-injected target tumors were stable and 10/16 patients progressed at week 6. One patient had a 3-fold decrease in CEA and CA 19.9. Conclusions: This study showed that vectorized gene therapy of liver tumors with TG4023/5-FC combination is feasible and safe, as supported by a high therapeutic index; MTD for TG4023 was 4.108 pfu for one injected tumor. A proof of concept of the in vivo conversion of the pro-drug 5-FC into 5-FU was obtained.
Evaluation of utility of pharmacokinetic studies in phase I combination trials.
Authors: Wu Kehua , House Larry , Ramirez Jacqueline , Ratain Mark J.
Published: March 2020

2611

Background: There are many phase I clinical combination trials including drug-drug interaction (DDI) studies, but very few of them report positive results. We hypothesized that the utility of DDI studies is low in the absence of a mechanistic hypothesis. Methods: We retrospectively reviewed 119 phase I (2 drug) combination studies published in 2007-2011. Results: Only 23 (19%) studies had a positive rationale, either inhibition/induction of a drug metabolizing enzyme or transporter, co-substrates for the same enzyme or transporter, potential for end-organ toxicity, or protein- binding. Only 9 (8%) studies demonstrated a statistically significant effect DDI, based on AUC of parent drug or active metabolite. There was a strong association between lack of rationale and a lack of interaction, as only 2% of studies without a rationale demonstrated a DDI, compared to 30% of studies with a rationale (Fisher’s exact test, p=0.0004) (Table). Conclusions: DDI studies should not be routinely performed as part of phase I clinical trials. [Table: see text]
A first-in-human phase I study of the oral p38 MAPK inhibitor LY2228820 dimesylate in patients with advanced cancer.
Authors: Goetz Matthew P. , Tolcher Anthony W. , Haluska Paul , Papadopoulos Kyriakos P. , Erlichman Charles , Beeram Muralidhar , Lensing Janet , Rasco Drew Warren , Molina Julian R. , Arcos Rebecca , SHI Peipei , Kulanthaivel Palaniappan , Pitou Celine , Mulle Lynette , Chan Edward Michael , Patnaik Amita
Published: March 2020

3001

Background: p38 MAPK regulates production of cytokines by the tumor microenvironment and its activation enables cancer cells to survive in the presence of oncogenic stress, radiation, chemotherapy, and targeted therapies. LY2228820 is a selective small-molecule inhibitor of p38 MAPK and preclinical studies demonstrate antitumor activity as a single agent and in combination with standard agents. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of LY2228820 and to characterize its pharmacokinetics and pharmacodynamics. Methods: Dose escalation was performed in a 3+3 design. LY2228820 was taken orally every 12 hours on days 1-14 of a 28-day cycle. Results: 54 patients received either capsules at 8 dose levels (10, 20, 40, 65, 90, 120, 160, and 200mg) or tablets at 5 dose levels (160, 200, 300, 420, and 560mg). For both formulations, Cmax and AUC increased in a dose-dependent manner. LY2228820 inhibited p38 MAPK induced phosphorylation of MAPKAP-K2 in peripheral blood with dose-dependent maximum inhibition from 10 to 70% across the dose range 10-200mg. The most common drug-related adverse events included fatigue, nausea, rash, constipation, vomiting, and pruritus. 1 patient (200mg) had DLT of erythema multiforme (Gr3) and 2 patients (560mg) had DLT of ataxia (Gr3) and dizziness (Gr2), respectively. Although the MTD was 420mg, the frequency of Gr1/2 adverse events (mainly rash, dizziness, and tremor) and observation of clinical activity at lower dose levels led to a recommended dose of 300mg (mean AUC0-24 = 11.7ug-hr/ml at steady state). Early clinical activity has been observed in ovary, breast, and kidney cancers. One patient with metastatic clear cell carcinoma of the kidney refractory to sorafenib, sunitinib, and temsirolimus had confirmed near partial response (29% decrease) after 8 cycles and remains on therapy. 15 patients (28%) achieved best overall response of stable disease, which in 12 patients (22%) was prolonged (≥4 cycles). Conclusions: LY2228820 demonstrates acceptable pharmacokinetics, safety, and early clinical activity as a single agent in advanced cancer. A phase II study for patients with ovary cancer is planned.
First-in-human phase I trial of the dual mTORC1 and mTORC2 inhibitor AZD2014 in solid tumors.
Authors: Banerji Udai , Dean Emma Jane , Gonzalez Michael , Greystoke Alastair P , Basu Bristi , Krebs Matthew , Puglisi Martina , Grinsted Lynda , Oelmann Elisabeth , Burke Wendy , Harrington Elizabeth , Green Stephen , Ranson Malcolm
Published: March 2020

3004

Background: AZD2014 is a potent, dual mTORC1/mTORC2 inhibitor with clear activity in in vivo and in vitro experimental models. Methods: This 2-part study consisted of "rolling six" dose escalation (Part A) and expansion (Part B) phases. Part A: 3–6 pts per cohort received an oral solution of AZD2014 BD starting at 50 mg. A further 6 pts were treated in Part A below the MTD to study changes in pharmacodynamic (PD) biomarkers. Part B: additional pts were dosed at the MTD, including a group of ER+/PR+ or HER2+ patients with breast cancer. Primary endpoint: safety and tolerability; secondary endpoints: pharmacokinetics (PK), PD and efficacy. Biomarkers assessed: mTORC1: pS6 (S235/236) and p4EBP1 (T37/46); mTORC2: pAKT (S473). Results: 50 pts have been enroled in this ongoing study and interim data are reported: Part A, n=23 (25 mg, n=6; 50 mg, n=8; 70 mg, n=5; 100 mg, n=4; all BD); Part B, n=27. The MTD was 50 mg BD. DLTs were seen at both 100 mg (Gr 2 and 3 lethargy/fatigue, n=4/4) and 70 mg (Gr 3 mucositis, Gr 2 lethargy, n=2/4); no DLTs were seen at 25 mg or 50 mg. The most common AEs in order of incidence were fatigue, stomatitis, decreased appetite, nausea and diarrhea. Seven SAEs (nausea, vomiting, lethargy, abdominal pain, mucositis) reported by 3 pts were considered ‘possibly related’ to the study drug by investigators. AZD2014 is rapidly absorbed following single and BD multiple doses with a short t1/2 of ~3 h. At 50 mg (n=32), preliminary data show geometric mean AUCss=7.4 µg.h/ml and Cmax ss=1.7 µg/ml. One pt with acinar pancreatic cancer had a RECIST partial response. pAKT and p4EBP1 reductions were observed between 2–8 h in platelet-rich plasma and peripheral blood mononuclear cells respectively. Target modulation in paired tumor biopsies was seen at the MTD. Reduction in the phosphorylation of S6 and 4EBP1 was evident in 8/10 and 3/9 paired biopsies respectively. pAKT was reduced in 3/6 evaluable paired biopsies. As opposed to rapalogs, pAKT was not upregulated in any of the evaluable post-treatment biopsies. Conclusions: The MTD for AZD2014 is 50 mg BD. Further clinical evaluation of AZD2014 is now warranted based on the safety, PK and proof-of-mechanism PD data, as well as its preliminary clinical activity. Updated results will be presented.
A first-in-human phase I study of oral pan-CDK inhibitor BAY 1000394 in patients with advanced solid tumors: Dose escalation with an intermittent 3 days on/4 days off schedule.
Authors: Bahleda Rastislav , Gazzah Anas , Varga Andrea , Rajagopalan Prabhu , Henderson David Andrew , Kornacker Martin , Soria Jean-Charles
Published: March 2020

3012

Background: BAY 1000394 (BAY) is an oral pan-CDK inhibitor targeting CDKs 1,2,4, 7 and 9 in the low nanomolar range. A phase I dose escalation study was initiated to determine the maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) in patients (pts) with advanced solid tumors. Methods: BAY was administered twice daily in a 3 days on / 4 days off schedule (cycle length 21 days, 3+3 design). PK was evaluated on cycle 1 day 1 and day 10. Response rate was assessed according to RECIST 1.1. PD markers included CK18 fragments in plasma. Results: As of Jan 08 2011, 34 pts were treated at doses of 0.6 (3 pts), 1.2 (4), 2.4 (3), 4.8 (3), 9.6 (3), 19.2 (6) mg per day as oral solution and at doses of 10 (4), 15 (6) and 20 (2) mg per day as tablet. Tumor types included 10 colorectal, 4 mesothelioma and 20 others. Cohort 9 (20 mg tablet) is ongoing. Frequent CTCAEv4 grade 1/2 drug related AEs occurring in more than 25% of patients up to cohort 8 were asthenia, diarrhea, nausea, vomiting and anorexia. DLTs (grade 3, 1 pt each) were hyponatremia, aphtous stomatitis at 19.2 mg solution and arterial thrombosis at 15 mg tablet. Aphthous stomatitis (20%) has not been observed with the tablet formulation. Other grade 3 related AEs were asthenia in 2 and nausea and vomiting in one pt each. Nausea and vomiting on treatment days were observed despite antiemetic treatment (aprepitant +/- setron). PK was dose proportional up to 9.6 mg, T1/2 was 10 hours, and relative bioavailability of tablet formulation was excellent; major metabolite levels were low (<10%). Levels of CK18 fragments did not correlate with dose or tumor response. Stable disease (SD) lasting for 2-4 months was observed in 9 patients, among others in 4 of 4 mesothelioma and 2 of 2 ovarian pts. One additional pt with cholangiocarcinoma has ongoing SD lasting for 5 months. One of the ovarian pts had a significant decline of CA125 lasting for 3 months. Conclusions: The tablet formulation of BAY 1000394 was better tolerated than oral solution. So far, doses up to a 15 mg per day with concomitant antiemetic treatment showed an acceptable tolerability. SD was observed in 10 of 25 heavily pretreated pts across cohorts 3 – 8.
Phase I study of oral rigosertib in patients with advanced solid tumors.
Authors: Bowles Daniel W. , Diamond Jennifer Robinson , Lam Elaine Tat , Messersmith Wells A. , Weekes Colin D. , Leong Stephen , Gore Lia , Lieu Christopher Hanyoung , Freas Elizabeth , Ren Chen , Wilhelm Francois , Eckhardt S. Gail , Jimeno Antonio
Published: March 2020

3017

Background: Rigosertib (ON 01910.Na) is a new multi-targeted inhibitor of several kinases, including polo-like kinase 1 and PI-3 kinase, and is in advanced trials for myelodysplastic syndrome and pancreatic cancer as an IV agent. An oral formulation with good oral bioavailability has entered phase 1 in patients (pts) with advanced solid tumors to determine the dose limiting toxicities (DLT), recommended phase II dose, pharmacokinetic (PK) profiles, and to document any antitumor activity of this compound. Methods: Pts with histologically confirmed solid tumors refractory to standard therapy were given escalating doses of rigosertib (70, 140, 280, 560, 700 mg) twice daily continuously. Doses were escalated until intolerable grade 2 or grade 3/4 toxicities, at which point the previous dose level was expanded to define the MTD. All pts were assessed for safety, PK, PD and response. Urinary PK assessments were also performed at the MTD. Results: 25 pts (median age= 59; median ECOG PS= 1) received a median of 6 weeks of therapy at 5 dose levels: (70 mg n=3; 140 mg n=2 ; 280 mg n=3; 560 mg n=10; 700 mg n=7). The DLT was dysuria at 700 mg and led to expansion at 560 mg bid. There were no DLTs in the expansion cohort. Grade 2/3 toxicities related to rigosertib included dysuria (5/1), cystitis (4/0), urinary frequency (3/0), hematuria (2/1), abdominal pain (2/0), pelvic pain (1/1), nausea (1/0), distention/bloating (1/0) and hyponatremia (0/1). Improvements in dysuria were seen with oral hydration and sodium bicarbonate. A confirmed PR occurred in 1 pt (HN squamous cell ca, 42+ weeks), and SD was observed in 2 pts with ovarian cancer (56 weeks, 28 weeks), and 1 pt each with pancreatic neuroendocrine (40 weeks), carcinoid (32 weeks), nasopharyngeal (24 weeks) and renal cell (32+ weeks) tumors. Preliminary PK data reveal plasma rigosertib levels above the predicted pharmacodynamically active levels. Conclusions: The MTD of oral rigosertib administered twice daily continuously is 560mg. Dysuria is the dose limiting and most common toxicity and can be managed with oral hydration and sodium bicarbonate. Antitumor activity has been observed. Final safety and efficacy results, plasma and urinary PK relationships, and mutational analyses from archival tissue will be presented.
A five-arm, open-label, phase I/lb study to assess safety and tolerability of the oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with chemotherapy or erlotinib in patients with advanced solid tumors.
Authors: Becerra Carlos , Infante Jeffrey R. , Garbo Lawrence E. , Gordon Michael S. , Smith David A. , Braiteh Fadi S. , Gandara David R. , Jotte Robert M. , Reckamp Karen L. , Janku Filip , Burris Howard A. , Bellew Kevin M. , Gardner Olivia S. , Liu Li , Cox Donna S , Peddareddigari Vijay Gopal Reddy , Blumenschein George R.
Published: March 2020

3023

Background: Trametinib, an oral MEK1/MEK2 inhibitor, has demonstrated single-agent clinical activity. In vitro studies of trametinib plus docetaxel (doc), pemetrexed (pem) and erlotinib (erl) showed enhanced growth inhibition of lung cancer cell lines with and without RAS/RAF mutations. Trametinib+doc significantly increased apoptosis compared with either agent alone. Methods: This is a two-part, five-arm, phase I/Ib, open-label study to evaluate the safety and tolerability of trametinib plus doc, erl, pem, pem+carboplatin (pem+carbo), or nab-paclitaxel (nab-pac) (NCT01192165). Part I is dose escalation in patients (pts) with advanced solid tumors; part II is dose expansion in pts with lung and pancreatic cancers. A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II regimen (RP2R) for each combination. Dose-limiting toxicities (DLTs) were determined during the first treatment cycle (21 days). Trametinib was started at 0.5 mg/day; chemotherapy was given at full recommended doses. Erl was escalated from 50 mg/day. Pharmacokinetic (PK) samples were collected pre-, and 1, 2, 3 and 6 hours post-dose. Results: As of January 2012, 80 pts have been enrolled across all arms except trametinib+nab-pac. Preliminary exposure results of trametinib+doc, erl, or pem suggest no PK drug-drug interaction. The predominant DLT for trametinib+doc without growth factors (MTD = 0.5 mg+60 mg/m2) was neutropenia. When administered with growth factors, trametinib+doc has been given up to 1.5 mg+75 mg/m2 with no DLTs. The predominant DLTs for trametinib+erl (MTD = 1 mg+100 mg) were diarrhea and mucositis and for trametinib+pem (MTD = 1.5 mg+500 mg/m2) were mucositis and febrile neutropenia. The MTD for trametinib+pem+carbo has not yet been determined. To date there are 5 PRs in the trametinib+doc group and 2 PRs in the trametinib+pem group. An NSCLC expansion cohort for trametinib+pem is enrolling. Conclusions: Trametinib+doc and trametinib+pem have shown acceptable tolerability and initial evidence of clinical activity.
First-in-human phase I study: Results of a second-generation non-ansamycin heat shock protein 90 (HSP90) inhibitor AT13387 in refractory solid tumors.
Authors: Mahadevan Daruka , Rensvold Diane M , Kurtin Sandra E , Cleary James M. , Gandhi Leena , Lyons John F. , Lock Victoria , Lewis Samantha , Shapiro Geoffrey
Published: March 2020

3028

Background: AT13387 is a second-generation potent, novel non-ansamycin HSP90 inhibitor (IC50 0.71 nM). AT13387 has good tissue distribution, long tumor t1/2 resulting in extended knockdown of client proteins in cells and animal models of gastric, prostate and melanoma. Methods: AT13387 was administered as a 1-hr IV infusion twice weekly on Days 1, 4, 8, 11, 15 and 18 (Part A) and then subsequently, weekly on Days 1, 8 and 15 (Part B) of a 28-day cycle in a standard 3+3 dose-escalation design. The primary endpoint was to determine the MTD; secondary endpoints included PK, PD, safety and tolerability. Results: As of 1 Dec 2011, 53 patients received 1–12 cycles of AT13387 (median 2). In Part A, AT13387 was evaluated at 5 doses (10, 20, 40, 80, 120 mg/m2). In Part B, 4 additional doses (150, 220, 260 and 310 mg/m2) were explored. Common treatment related toxicities (≥ 10%) included transient and reversible GI disturbance (vomiting, nausea, dry mouth, diarrhea, abdominal pain), fatigue, local infusion site irritation and systemic infusion-related symptoms including chills, rash, itch, cardiovascular (tachycardia, bradycardia, hypertension, hypotension), and visual changes (diplopia, transient flashes, delayed light/dark accommodation, blurred vision). Severity of infusion-related symptoms, GI toxicities, and fatigue at 310 mg/m2 prevented further dose escalation. A dose of 260 mg/m2 has been identified as the once weekly MTD and the study is currently accruing at this dose. Biological evidence of HSP90 inhibition, demonstrated by an increase in HSP70 in PBMCs, was detected at all doses and exhibited evidence of dose dependence. PK demonstrated dose proportionality, without significant accumulation. One durable RECIST PR (8 months) in an imatinib relapsed metastatic GIST patient with c-kit mutations in exons 11 and 17 was observed. Three SD ≥ 6 months (follicular cell thyroid carcinoma, metastatic uveal melanoma, GIST) were also observed. Conclusions: The MTD of AT13387, administered as a once weekly IV, is 260 mg/m2. All drug-related toxicities were generally reversible. Single-agent activity was observed. Dose expansion at MTD and phase II studies are ongoing.
The effect of bevacizumab on targeting of anti-epidermal growth factor receptor and anti-insulin-like growth factor 1 receptor antibodies.
Authors: Heskamp Sandra , Boerman Otto C. , Molkenboer-Kuenen Janneke D.M. , Oyen Wim J.G. , Van Der Graaf Winette T.A. , Van Laarhoven Hanneke W.M.
Published: March 2020

3035

Background: Bevacizumab and cetuximab are approved antibodies for treatment of patients with metastasized colorectal cancer. However, the combination of bevacizumab and cetuximab does not improve progression free survival (Tol et al. NEJM 2009). This may be explained by the disruption of tumor vascularity by bevacizumab, thereby reducing targeting of other antibodies to the tumor. The aim of this study was to determine the effect of bevacizumab on the targeting of anti-EGFR and IGF-1R antibodies in tumors with SPECT/CT imaging. Methods: Mice with subcutaneous EGFR and IGF-1R-expressing SUM149 xenografts were injected intraperitoneally with a single dose of bevacizumab (10 mg/kg). After four days, mice received an intravenous injection of 17 MBq 111In-labeled cetuximab, an anti-EGFR antibody, or R1507, an anti-IGF-1R antibody. A control group was injected with labeled hLL2 anti-CD22, an irrelevant IgG . Three days after injection, SPECT/CT images were acquired and mice were dissected for ex vivo biodistribution. Tumors were analyzed immunohistochemically to determine vascular density (CD34), EGFR and IGF-1R expression. Results: SPECT imaging revealed that bevacizumab treatment reduced targeting of anti-EGFR and anti-IGF-1R antibodies by 42% and 35%, respectively. Ex vivo biodistribution showed that uptake of 111In-cetuximab in untreated tumors was 35.2 ± 1.6 %ID/g, compared with 19.7 ± 5.3 %ID/g for bevacizumab treated tumors (p = 0.009). A similar effect was observed for 111In-R1507 (control: 26.7 ± 2.8 %ID/g, bevacizumab:18.9 ± 2.8 %ID/g, p =0.009). No significant differences in tumor uptake were observed in mice that received the irrelevant IgG. Immunohistochemical analysis showed that vascular density decreased with 40%, while EGFR and IGF-1R expression was unaltered. Conclusions: Bevacizumab treatment can significantly reduce targeting of other antibodies to tumors. This underlines the importance of timing and sequencing of bevacizumab therapy in combination with other antibodies.
Phase I, first-in-human trial of an oral VEGFR tyrosine kinase inhibitor (TKI) x-82 in patients (pts) with advanced solid tumors.
Authors: Moore Kathleen N. , Jones Suzanne Fields , Kurkjian Carla , Arkenau Hendrik-Tobias , Infante Jeffrey R. , Pant Shubham , Burris Howard A. , McMeekin D. Scott , Gibbons Jay , Harrow Kimberly , Liang Chris , Ramsey Sara , Bendell Johanna C.
Published: March 2020

3041

Background: VEGFR TKIs have shown benefit in the treatment of various tumor types. Side effects of the TKIs have affected the duration of therapy pts can tolerate, as well as the combinability with chemotherapy. X-82 is a highly potent VEGFR/PDGFR TKI with a smaller volume of distribution and limited tissue accumulation designed to minimize side effects while maintaining target effect. Methods: Pts with advanced solid tumors were enrolled using an accelerated titration scheme followed by 3+3 dose escalation design. X-82 was administered orally once daily (QD) or twice daily (BID) every 28 days. Safety, pharmacokinetic, clinical endpoints and blood-based biomarkers were evaluated. Results: 16 pts were treated across 8 dose levels: 20 (n=1), 40 (n=1), 80 (n=1), 160 (n=1), 300 (n=2), 400 mg QD (n=3), 140 mg BID (n=3) and 200 mg BID (n=4). The most common related adverse events (AEs) by pt were fatigue (4 G1, 1 G2), nausea (3 G1, 1 G2), diarrhea (3 G1), anorexia (1 G1, 1 G2), and vomiting (2 G1). G2 hypertension, resolved with treatment, was experienced by 1 patient. No > G3 related AEs have been reported. Dose proportional exposure was observed with doses up to 160 mg QD, and BID dosing cohorts were added. At 160 mg QD X-82 has plasma concentrations >100 ng/mL for at least 12 hours, the desired exposure predicted preclinically. Preliminary blood biomarker data (n=8) shows >25% decrease in VEGFR1 in 62% of pts and in VEGFR2 in 25% of pts, including pts at 40 and 80 mg cohorts. Efficacy has also been noted, including 1 confirmed complete response lasting 24+ weeks (pancreatic adenocarcinoma), and 6 pts with stable disease lasting 8+ weeks (range 12.1+, 38.3+ weeks), including the pt at 20 mg with SCLC (25.1 weeks). Conclusions: X-82 is a well-tolerated VEGFR/PDFGR TKI designed to minimize side effects while inhibiting target receptors. No MTD has yet been defined, though preliminary biomarker data are encouraging and clinical efficacy has been noted.