bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I trial of belinostat in combination with cisplatin (Cis) and etoposide (Etop).
Authors: Balasubramaniam Sanjeeve , Bryla Christina , Redon Christophe E. , Lee Min-Jung , Peer Cody , Trepel Jane B. , Rajan Arun , Bonner William , Figg William Douglas , Fojo Antonio Tito , Piekarz Richard , Giaccone Giuseppe , Bates Susan Elaine
Published: March 2020

2527

Background: Histone deacetylase inhibitors (HDIs) are epigenetic therapies in development. To exploit the unique activity in impairing DNA repair, HDIs have been combined with chemotherapy. Belinostat is a potent HDI combined with Cis and Etop based on enhanced DNA damage and apoptosis in small cell lung cancer (SCLC) cells. Methods: Patients with relapsed/refractory cancer or previously untreated advanced stage SCLC were eligible. Belinostat was administered by continuous infusion (CIV) over 48h, from 400 mg/m2/24h, in cohorts of 3. Cis was administered on day 1 and Etop daily X3. Belinostat pharmacokinetics (PK) and several pharmacodynamic (PD) measures were assessed, including lysine acetylation in peripheral blood mononuclear cells (PBMCs) and γH2Ax staining in PBMCs and in hair follicles. Results: Five dose levels were explored in 20 patients with solid tumors, including 5 patients with SCLC, two who had no prior therapy. At the first dose level, dose-limiting toxicities (DLT) of gr 4 ANC in 1, and gr 3 HTN in 1 were observed. Cis and Etop were reduced to 60 mg/m2 and 80 mg/m2, respectively, and the dose level repeated without DLT. At the next dose level, 800 mg/m2/24h belinostat, grade 3 HTN and grade 4 pneumonitis were observed. At the MTD of 600 mg/m2/24h belinostat, DLT was seen in 1 of 6 pts; however, all 6 pts required later dose reductions. We thus considered 500 mg/m2/24h in combination with Cis and Etop to be the recommended Phase II dose; confirmation ongoing. PKs show belinostat levels at 1 uM over the 48h infusion, decreasing rapidly to the 60h timepoint. In total 11 pts, 3 with SCLC, completed 6 cycles. PR was seen in 6 pts (3 with SCLC). PD studies confirmed γH2AX staining in PBMCs and hair follicles, peaking at 36h and 60h, respectively. Tubulin and lysine acetylation (Ac-K) in PBMCs peaked at 36h; Ac-K recovered more rapidly than tubulin, mirroring γH2AX. Conclusions: The MTD of belinostat over 48h by CIV was 600 mg/m2/24h, in combination with Cis 60 mg/m2 on day 1 and Etop 80 mg/m2 on days 1 - 3. PD endpoints indicate that belinostat is active in promoting both acetylation and DNA damage. The HDI combined with chemotherapy requires dose reduction and likely represents an on-target increase in DNA damage. Clinical trial information: NCT00926640.
Phase I study of safety, tolerability, and pharmacokinetics of pazopanib in combination with oral topotecan in patients with advanced solid tumors.
Authors: Milojkovic Kerklaan Bojana , Lolkema Martijn P. J. K. , Devriese Lot A. , Voest Emile E. , Nol-Boekel A. , Mergui-Roelvink M. , Mykulowycz Kristine , Stoebenau Joseph E , Fang Lei , Legenne Philippe , Wissel Paul Stephen , Smith Deborah A. , Giantonio Bruce J. , Schellens Jan HM , Witteveen Petronella
Published: March 2020

2536

Background: To determine the maximum-tolerated dose (MTD), safety, tolerability and pharmacokinetics of the oral anti-angiogenic drug pazopanib in combination with oral topotecan, an inhibitor of topoisomerase-I. Methods: Two-stage, two-arm, dose escalation and pharmacokinetic phase I study of pazopanib and oral topotecan in patients with advanced solid tumors, (NCT00732420, www.clinicaltrials.gov). This interim report describes the bioavailability and safety results for daily pazopanib combined with oral topotecan (days 1, 8, 15) in a 28-day cycle. Results: Twenty-eight of 32 patients completed at least one cycle and were evaluable for analysis. Three dose-limiting toxicities (DLTs) occurred: grade 3 hand-foot-syndrome, diarrhea and neutropenia. Pazopanib 800 mg/topotecan 10 mg exceeded the MTD with two DLTs in six patients. The most frequent treatment-related toxicities were grade 3 anemia (3/28), leukocytopenia, neutropenia and fatigue (2/28 each). One death due to hepatic failure occurred at pazopanib 800mg/toptecan 2mg in a heavily pre-treated patient with sarcoma that may have been related to paracetamol ingestion but attribution to the pazopanib can not be excluded. Topotecan AUC0-∞ increased 1.58-fold (90%CI: 1.09–1.29) and Cmax increased 1.78-fold (90%CI: 1.08-2.92) when given with pazopanib compared to single administration (n=7). Pazopanib AUC0-24 and Cmax ratios were not increased when co-administered with topotecan: 0.98 (90%CI: 0.95-1.02) and 0.96 (90%CI: 0.92-1.01). Twenty-three patients were evaluable for response (RECIST): PR (2/23; 9%, both ovarian cancer); SD (13/23; 57%) and PD (8/23; 35%). Pazopanib 800 mg/topotecan 8 mg is currently being explored in an expansion cohort. A second treatment arm of pazopanib 800 mg with topotecan daily x5 is ongoing and will be reported separately. Conclusions: Daily pazopanib and weekly oral topotecan is tolerable with handfoot syndrome, neutropenia and fatigue as dose limited side effects. Pazopanib increased topotecan exposure 1.58-fold (AUC0-∞) and 1.78-fold (Cmax). Clinical trial information: NCT00732420.
A phase I trial and pharmacokinetic study of trebananib (AMG386) in children with recurrent or refractory solid tumors: A Children’s Oncology Group Phase 1 Consortium report.
Authors: Leary Sarah , Park Julie R. , Reid Joel M. , Ralya Andrew T. , Baruchel Sylvain , Wu Bing , Ingle Ashish M , Ahern Charlotte H , Weigel Brenda , Blaney Susan
Published: March 2020

2538

Background: Trebananib is a first-in-class peptibody (peptide-Fc fusion protein) that selectively inhibits Angiopoietin 1 and Angiopoietin 2 to inhibit interaction with the Tie2 receptor tyrosine kinase and prevent angiogenesis by a VEGF independent mechanism. A pediatric phase 1 trial was performed to define the dose limiting toxicities (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of trebananib. Methods: Trebananib was administered as a weekly 30 - 60 minute IV infusion. Three dose levels (10, 15 or 30 mg/kg/dose) were evaluated using a rolling-six design. PK sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks of therapy. Results: Fifteen eligible patients (14 evaluable for toxicity) with a median age of 14 yrs (range, 3 to 20) and diagnoses of neuroblastoma (n=4), rhabdomyosarcoma (n=3), Ewing sarcoma (n=3), osteosarcoma (n=2), other soft tissue sarcoma (n=2), or nasopharyngeal carcinoma (n=1) have been enrolled. There were no DLTs observed at either the 10 mg/kg (n=6 pts) or 15 mg/kg (n=3 pts) dose. 1/6 pts receiving 30 mg/kg/dose developed DLT (venous thrombosis at a central line site). Non-dose limiting grade 3 or 4 toxicities included lymphopenia (n=2) hypertension (n=1), and neutropenia (n=1). Response in evaluable patients after eight weeks of therapy included stable disease (n=6 pts) and progressive disease (n=7 pts). PK were linear over the 3 dose levels, with t1/2 and Clpvalues of 69±18 h and 1.6±0.5 ml/h/kg, respectively. Conclusions: Trebananib is well tolerated in pediatric patients with recurrent or refractory solid tumors with recommended Phase 2 dose of 30 mg/kg. Correlative biology studies will be presented. Further study is planned to evaluate tolerability and changes in vascular permeability in patients with primary CNS tumors. Clinical trial information: NCT01538095.
Treatment of cancer and cancer stem cells by blocking the Notch pathway.
Authors: Epenetos Agamemnon A. , Stylianou Spyros
Published: March 2020

2539

Background: Current treatments often fail to cure cancer. It has been shown (JCO, 26, June 10, 2008) that Cancer Stem Cells, (CSCs), are responsible for the initiation, metastasis and recurrence of many cancers and may be a key reason for the failure of current therapies.The NOTCH pathway is an important pathway in the development of many tumors ,and cancer stem cells in particular. Methods: We have generated genetically and synthetically a hybrid protein (Antp-DNMAML) .consisting of the truncated version of MastermindElike (MAML) that behaves in a dominant negative (DN) fashion inhibiting Notch activation, and the cell penetrating peptide Antennapedia (Antp). Results: It is demonstrated that Antp-DNMAML translocates into the nucleus and suppresses Notch activation. Attenuation of Notch signaling with AntpEDNMAML reverts the transformed phenotype, inhibits the anchorageEdependent growth, induces self contact inhibition and apoptosis in highly tumorigenic epithelial human breast cancer cells. More significantly, we provide direct evidence that inhibiting Notch signaling at the transcriptional level with the Antp-MAML protein ,suppresses the expression of downstream Notch targets, induces tumor cell apoptosis, and inhibits or eliminates human tumor growth in nude mice, without organ or systemic toxicity. Conclusions: Intracellular delivery of dominant-negative transcription complex proteins using the Antp platform is a new and specific approach for cancer therapy.
Effects of a soluble activin type 2B receptor Fc fusion protein (STM 217) in TOV-21G, a mouse xenograft model of clear cell ovarian cancer.
Authors: Lu John , Haqq Christopher M. , Han HQ
Published: March 2020

2541

Background: Response rate and survival with the clear cell subtype of ovarian cancer is has not been improved by the introduction of platinum and taxane chemotherapy. Elevated serum activin is associated with inferior ovarian cancer survival, suggesting that activin inhibition may provide a new treatment strategy. STM 217 (recombinant hu-sActR2B-Fc) is a potent (IC50 < 1nM) inhibitor of activin and myostatin signaling that was tested for anti-ovarian tumor activity. Methods: Athymic nude mice received TOV-21g (clear cell ovarian cancer model) xenografts in the abdominal flank region and after 14 days, weekly subcutaneous STM 217 was administered alone or in combination with 5-fluorouracil (5-FU). Mice were monitored for body weight and tumor volume. Results: After 52 days from tumor cell injection, STM 217 treatment resulted in a statistically significant 43% (p<0.0001) tumor growth reduction, versus the vehicle-treated tumor bearing group tested using ANOVA. In the combination efficacy experiment, 5-FU monotherapy resulted in a 47% (p<0.0001) tumor growth reduction, and the combination of STM217 and 5-FU together resulted in a 73% (p<0.0001) tumor growth reduction. During the course of the study, body weight of the mice receiving STM 217 increased by 26%, mice receiving STM 217 and 5-FU increased by 22%, while control tumor bearing mice receiving vehicle exhibited a 10% body weight loss. Conclusions: Our study demonstrates that inhibition of activin signaling by use of a ligand trap results in antitumor activity, both as a monotherapy, and that additive activity was observed in combination with chemotherapy. Increases in body weight were not impaired by concomitant administration of 5-FU chemotherapy. This study suggests that a phase 1 clinical trial of activin inhibition in metastatic ovarian cancer is warranted.
Phase Ib trial of combining aldoxorubicin plus doxorubicin.
Authors: Sankhala Kamalesh Kumar , Chawla Sant P. , Chua Victoria S , Quon Doris , Bonk Allison , Narasimhan Vivek , Sodhi Monish , Krishna Nina , Dinh Hillary , Wieland Scott , Levitt Daniel
Published: March 2020

2550

Background: Aldoxorubicin is a novel drug that covalently binds to albumin in the circulation with release in low pH environments. Preclinical studies in pancreatic and ovarian tumor xenograft models demonstrated that aldoxorubicin plus doxorubicin administered at 50% of their MTD provided complete and prolonged tumor remission in these models with less toxicity than each drug administered at their MTD. We evaluated the toxicity profile of a fixed dose of doxorubicin and escalating doses of aldoxorubicin in subjects with advanced solid tumors. Methods: Phase 1b open label, dose-escalation study of aldoxorubicin administered at either 175, 240 or 320 mg/m2 (130, 180, or 240 mg/m2 doxorubicin equivalents) iv + 35 mg/m2doxorubicin iv, both on Day 1 of 21 day cycles, for up to 8 cycles. The MTD is the dose level immediately below where 2/6 subjects experience a dose limiting toxicity (DLT) , or the maximum dose of 320 mg/m2aldoxorubicin. Additional subjects may be enrolled at the MTD to provide more safety data. Results: 10 subjects have been treated as of January 21, 2013. No DLT was observed and the MTD was defined as 320 mg/m2 aldoxorubicin and 35 mg/m2 doxorubicin iv administered on Day 1 of 21 day cycles. A median of 4.5 cycles have been received. 3/10 subjects were terminated due to either progressive disease (2) or death (1). No subject was terminated due to an adverse event. Grade 3 or 4 neutropenia was seen at all dose levels (8/10 subjects). 4/10 subjects exhibited grade 3 or 4 thrombocytopenia and 3/10 subjects had grade 3 or 4 anemia. Neutropenic fever occurred in 3/10 subjects. Other grade 3/4 adverse events seen in 2 or fewer subjects included fatigue, increased liver enzymes and dehydration. No significant mucositis or cardiotoxicity was observed. At this time the best response has been stable disease in 6/10 subjects and a partial response in 1 subject (malignant fibrous histiocytoma). Conclusions: The combination of aldoxorubicin (320 mg/m2)) + doxorubicin (35 mg/m2) can be safely administered to subjects with solid tumors. Hematologic toxicity is common and can be controlled with growth factors. The dose of aldoxorubicin is 90% of the MTD of aldoxorubicin administered as a single agent. Thus, doxorubicin does not appear to add to the toxicity of this combination. Clinical trial information: NCT01673438.
Phase I trial and pharmacokinetic (PK) study of satraplatin in children and young adults with refractory solid tumors including brain tumors.
Authors: Akshintala Srivandana , Marcus Leigh , Warren Katherine E. , Murphy Robert F. , Goodspeed Wendy J. , Goodwin Anne , Brewer Carmen C. , Zalewski Christopher , King Kelly A. , Kim AeRang , Widemann Brigitte C.
Published: March 2020

2554

Background: Satraplatin is an orally bioavailable platinum analog. Based on pre-clinical activity (IC500.02-8 µg/ml) including activity in cisplatin resistant cell lines, and clinical activity without neuro-, nephro-, or ototoxicity in adults with refractory tumors, we developed a phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and PKs of satraplatin in children with refractory solid tumors. Methods: Satraplatin (10 and 50 mg capsules) was administered orally once daily on days 1 - 5 of a 28 day cycle to cohorts of 3-6 patients (pts) at 60 mg/m2/dose (DL 1) and 80 mg/m2/dose (DL 2). Plasma ultrafiltrate (PUF) platinum was measured using atomic absorption spectroscopy during cycle 1 for PK analysis. Results: 9 pts [5 male, 4 female, median age 17 years (range 8-19)] with malignant glioma (n=4), ependymoma (n=2), medulloblastoma (n=1), osteosarcoma (n=1), or hepatoblastoma (n=1) received 1-10+ cycles (median 2). The MTD was exceeded at DL 2 as 2/4 pts had dose limiting toxicities (DLT) of delayed and prolonged myelosuppression (grade 3 thrombocytopenia, n=1; grade 3-4 neutropenia, n=2). 0/5 pts at DL 1 had DLTs. Grade 1 ototoxicity was seen in 1 pt at cycle 10. Non-DLTs included myelosuppression, gastrointestinal toxicities, fatigue, headache, liver enzyme elevation, and electrolyte abnormalities. No objective responses were observed, but 1 pt with gliomatosis cerebri has had radiographic stable disease through cycle 10+. Satraplatin mean exposure (AUC) and peak concentration (Cmax) were similar at both dose levels [day 1 PUF AUC0-24h 1.22 ± 0.55 µg/ml*h at DL1 (n=3), 1.02 ± 0.45 µg/ml*h at DL2 (n=3); Cmax0.17 ± 0.08 µg/ml at DL 1 (n=3), 0.16 ± 0.05 µg/ml at DL 2 (n=3)]. Terminal half-life was 14 ± 6 h and apparent clearance was 76 ± 29 L/h (n=6). Conclusions: The MTD of oral satraplatin in children with solid tumors is 60 mg/m2/dose daily x 5 q28 days. The toxicity profile was similar to adults, and delayed myelosuppression was DLT. Satraplatin exposure appears higher in pediatric pts compared to adults (PUF AUC0-24h 0.25-0.47 µg/ml*h at 60-80 mg/m2/dose). DL 1 will be expanded to gain additional experience regarding toxicities and PKs in a broader age range. Clinical trial information: NCT01259479.
Clinical pharmacokinetics (PK) and translational PK-pharmacodynamic (PD) modeling and simulation to predict antitumor response of various dosing schedules to guide the selection of a recommended phase II dose (RP2D) and schedule for the investigational agent MLN0128.
Authors: Patel Chirag G. , Patel Mayank , Chakravarty Arijit , Gangolli Esha A. , Barry Elly , Westin Eric H. , Jessen Katti , Chitnis Shripad D. , Infante Jeffrey R. , Gordon Michael S. , Macarulla Teresa , Cervantes-Ruiperez Andres , Jalal Shadia Ibrahim , Venkatakrishnan Karthik
Published: March 2020

2567

Background: MLN0128 (INK128) is an investigational oral, potent, and highly selective inhibitor of mammalian target of rapamycin complex 1 and 2 (mTORC1/2) currently in clinical investigation. In the phase1 study INK128-001, MLN0128 was administered once daily (QD), once weekly (QW), QDx3D/week, and QDx5D/week, with respective MTDs of 6, 40, 16, and 10 mg. To guide selection of dose/schedule for further investigation, PD modulation in skin (pS6, p4EBP1, pNDRG1, pPRAS40) was put into context of clinical PK in INK128-001. A preclinical translational dynamic-PK efficacy model was used to describe the relationship and determine PK drivers of efficacy in tumor xenograft models. This model was implemented using human PK parameters to predict tumor volume-time curves, which was utilized to help determine the optimal MLN0128 dose/schedule. Methods: Phoenix NLME v1.1 was used for compartmental modeling of clinical and preclinical PK data, and modeling the preclinical PK-efficacy relationship of MLN0128. PD activity in skin was measured by immunohistochemistry, reported as H scores. Tumor growth curves were simulated using NONMEM v7.2; predicted tumor growth curves were plotted in S-Plus v8.1. Results: Clinical skin PD data suggests exposure dependent inhibition of pS6, and p4EBP1. A two compartment PK model adequately described the PK characteristics of MLN0128 [mean (%CV) ka: ~5.305 h-1 (114), k12: ~0.490 h-1(85), k21: ~0.67 h-1(69), V/F: ~180 L (44), Tlag: 0.317 h (73)]. Simulation of human tumor volume-time curves suggest efficacy is dependent on schedule and that MLN0128 administered in more frequent schedules (QD, QDx5D) provides stronger antitumor effect vs less frequent schedules (QW, QDx3D). Conclusions: The results indicate that per unit MLN0128 plasma exposure, QD and QDx5D may be optimal in comparison with QDx3D and QW dosing. However, these results will also need to be put into context with the overall safety profile and respective MTDs and RP2Ds for each schedule with their resultant achievable total cycle dose by schedule. Clinical trial information: NCT01058707.
Dose-ranging randomized pharmacokinetic (PK) and pharmacodynamic (PD) study of vorinostat in patients with advanced solid tumors.
Authors: Gangadhar Tara C. , Beumer Jan Hendrik , Espinoza-Delgado Igor , Anyang Bean N. , Karovic Sanja , Sharma Manish , Wen Yujia , Janisch Linda A. , Kindler Hedy Lee , Nanda Rita , Karrison Theodore , Ratain Mark J. , Maitland Michael L.
Published: March 2020

2571

Background: Continuous 400 mg daily vorinostat (V) is effective treatment for cutaneous T-cell lymphoma, but has displayed erratic activity in combination therapy for solid tumors. Short-course high-dose vorinostat may have a better therapeutic index for solid tumors, but dose/exposure/PD relationships have not been tested in sufficiently powered studies. Methods: Patients (pts) were randomized to either V 1600 mg daily, days (d) 1-3 then 400 mg d8-10 or 400 mg d1-3 then 1600 mg d8-10 with complete PK sampling on d3 and d10 to determine the increase in Cmax upon increasing V from 400 to1600 mg. To assess safety and tolerability of high dose V added to carboplatin, pts then received high dose V d15-17 with carboplatin AUC 5 on d17; this combination was repeated every 21d thereafter. Platelet counts were determined weekly. To detect with 80% power a difference in vorinostat Cmax between 400 and 1600 mg required at least 10 pts in each sequence. In vitro studies of gene expression in solid tumors suggested as a secondary endpoint the frequency of pts achieving Cmax > 1000 ng/mL. Results: 24 pts (11 men/13 women) enrolled between April 2011 and March 2012 and were evaluable for study endpoints. No sequence dependence of change in Cmax was detected. Cmax for V 1600 mg was nearly double that for 400 mg (1184+/-631 vs. 616+/-442 ng/mL, p < 0.001). The PD effect on platelets (d10) was greater for the higher dose (median -76 vs. -14 K/µL, p= 0.02). There were no dose limiting toxicities. Of 24 pts, 11 achieved Cmax > 1000 ng/mL. Conclusions: The 1600 mg dose of vorinostat results in a higher Cmax than 400 mg and greater PD effect than 400 mg and is tolerable in combination with carboplatin. The carboplatin/vorinostat doublet serves as a DNA-damaging/epigenetic modifier module to be combined in more complex regimens. Clinical trial information: NCT01281176.
A phase I, first-in-human study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of IMGN853 in patients (Pts) with epithelial ovarian cancer (EOC) and other FOLR1-positive solid tumors.
Authors: Kurkjian Carla , LoRusso Patricia , Sankhala Kamalesh Kumar , Birrer Michael J. , Kirby Maurice , Ladd Sharron , Hawes Susan , Running Kelli Lynn , O'Leary James J. , Moore Kathleen N.
Published: March 2020

2573

Background: IMGN853 is an antibody-drug conjugate (ADC) comprising a folate receptor 1 (FOLR1)-binding antibody and the potent maytansinoid, DM4. FOLR1 is over-expressed on many solid tumors, particularly EOC, endometrial cancer, non-small cell lung cancer (NSCLC), and clear-cell renal cell cancer. Methods: The primary study objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives include evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy. In dose escalation, patients with any type of FOLR1-expressing, refractory solid tumor may be enrolled. Once the MTD is defined, 3 expansion cohorts will evaluate patients with (1) primary platinum refractory or resistant EOC; (2) relapsed/refractory EOC, amenable to biopsy, and (3) relapsed/refractory NSCLC. Cohorts 2 and 3 will have IMGN853 PD assessment by pre-and post-dose tumor biopsy and by FLT-PET imaging, respectively. IMGN853 is given intravenously (IV) on Day 1 of each 21-day cycle. During dose escalation, an accelerated titration design was used. Responses are assessed using RECIST and GCIG criteria (as appropriate). Results: Eleven patients have been enrolled across 6 dose levels ranging from 0.15 to 5.0 mg/kg: 7 patients with EOC and 4 patients with endometrial cancer. No study drug-related serious adverse events (SAEs) or dose-limiting toxicity (DLT) have been reported. Among these 11 patients, 3 patients reported adverse events (AEs) considered study drug related; these were mild or moderate. At the 3.3 mg/kg dose level, one patient with serous EOC had an 82% reduction in CA125 (confirmation pending). The other 2 patients at this dose level, one with EOC and one with endometrial cancer, have stable disease. Drug exposure has been measured in 8 patients and has been found to generally increase linearly, with a half life at 3.3 mg/kg (3 patients) of approximately 4 days. Conclusions: IMGN853 is well tolerated at doses up to 3.3 mg/kg. Safety evaluation continues at 5 mg/kg and dose escalation is ongoing. Clinical trial information: NCT01609556.
Phase IB study of olaparib (AZD2281) plus gefitinib in EGFR-mutant patients (p) with advanced non-small-cell lung cancer (NSCLC) (NCT01513174/GECP-GOAL).
Authors: García Campelo Rosario , Felip Enriqueta , Massuti Bartomeu , Majem Margarita , Carcereny Enric , Cardenal Felipe , Molina-Vila Miguel Angel , Martinez Marti Alex , Marti-Ciriquian Juan Luis , Alonso-Jaudenes Curbera Guillermo , Pallares Cinta , Palmero Ramon , Gonzalez-Arenas Maria Carmen , Mayo-de las Casas Clara , Sanchez-Ronco Maria , Rosell Rafael
Published: March 2020

2581

Background: Progression-free survival (PFS) and response to EGFR tyrosine kinase inhibitors (TKIs) vary in p with NSCLC driven by EGFR mutations. In our experience, high BRCA1 mRNA expression was associated with shorter PFS in EGFR-mutant p treated with erlotinib. We hypothesized that since olaparib downregulates BRCA1 expression, the addition of olaparib to gefitinib could improve PFS in these p. Methods: This is a Phase IB dose escalation study to identify the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics, and clinical activity of orally administered olaparib in combination with gefitinib in EGFR-mutant advanced NSCLC p. In a standard 3+3 design, p were treated with gefitinib 250mg once daily plus olaparib tablets at escalating doses ranging from 100mg BID to 250mg TDS during a 28-day cycle. Results: 18 p have been included across four dose levels of olaparib: 100mg BID (3), 200mg BID (6), 200mg TDS (3) and 250mg TDS (6). Median age, 69; male, 4; PS 0, 17; EGFR TKI treatment-naïve, 10. Toxicities: anemia (66.6%), leucopenia (33.3%), nausea (33.3%), diarrhea (33.3%), asthenia (27.7%), rash (22.2%) vomiting (11%), decreased appetite (16%), and hyperlipasemia (5.5%). Most toxicities were G1-2; G3 drug-related events included leucopenia (1) and anemia (3). No DLT at dose levels 1, 2, and 3; 1 DLT at dose level 4 (G3 anemia and repeated blood transfusion within 4-6 weeks). Few dose reductions or interruptions were needed. 1 p died due to pulmonary embolism unrelated to treatment. Partial responses (PR) were observed in 7 p (41.1%), all EGFR TKI-naïve; stable disease (SD) in 7 (41.1%), most previously treated; progressive disease (PD) in 3 (17.6%), all previously treated. Durable PR and SD were observed in EGFR TKI-naïve and previously treated p. 8 patients are still on treatment. Enrollment to dose level 4 will be completed in February 2013. Conclusions: This phase IB trial of gefitinib plus olaparib, has confirmed the activity and tolerability of the combination. The final recommended dose of olaparib is expected to be between 200 and 250 mg TDS. A phase II randomized trial in treatment-naïve EGFR-mutant advanced NSCLC will be opened in 2013. Clinical trial information: NCT0151317.
A phase I dose-escalation and PK study of continuous oral rucaparib in patients with advanced solid tumors.
Authors: Kristeleit Rebecca Sophie , Shapiro Geoffrey , LoRusso Patricia , Infante Jeffrey R. , Flynn Michael , Patel Manish R. , Tolaney Sara M. , Hilton John Frederick , Calvert Alan Hilary , Giordano Heidi , Isaacson Jeffrey D. , Borrow Jennifer , Allen Andrew R. , Jaw-Tsai Sarah S. , Burris Howard A.
Published: March 2020

2585

Background: Rucaparib, a potent, oral small molecule inhibitor of poly (ADP-ribose) polymerase (PARP) 1 and -2, is being developed for treatment of homologous recombination repair deficient (HRD) ovarian cancer. This study evaluated oral rucaparib as monotherapy. Primary objectives were to define maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and PK of continuous oral rucaparib. Methods: A standard 3+3 dose escalation design was used. Intra-patient dose escalation was allowed. Patients (pts) aged ≥18 with advanced solid tumor that progressed on standard treatments were recruited. Rucaparib was taken orally qd or bid until disease progression. Plasma PK assessments included full profile, trough levels, and food effect. Results: 29 pts (median age 52 yrs [range 21-71]; 26 female; 15 ECOG PS=0; 17 breast cancer (BC), 7 ovarian/peritoneal cancer (OC), 5 other tumor) were enrolled in 6 dose cohorts to date (40, 80, 160, 300 and 500 mg qd, 240 mg bid). Evaluation of 360 mg bid rucaparib is nearly complete. No DLTs have occurred and no pts have discontinued treatment due to toxicity. Treatment-related adverse events (primarily CTCAE grade 1-2) reported in ≥2 of 29 pts include fatigue (n=5), anorexia (n=3), nausea (n=3), vomiting (n=3), and diarrhea (n=2). To date, two pts (1 OC, 1 BC; both BRCA1mut) treated with 300 mg qd rucaparib achieved PR at wk 6; both are ongoing in wk 17. An additional 10 pts (5 OC, 4 BC, 1 CRC; 7 BRCAmut, 2 BRCAunk, 1 BRCAwt) achieved best response of stable disease (SD) >12 wks thus far; 4 pts (3 OC, 1 BC) are ongoing at 17 (n=2) and 30 (n=2) wks. Overall disease control rate (CR+PR+SD>12 wks) in OC pts across all dose levels was 86% (6/7). Dose proportional PK was observed up to 500 mg qd with mean t1/2 of 15 h (range 4.3 - 29 h). Following qd dosing, steady state was achieved by Day 8. As expected, bid dosing increased trough levels above 2 µM target with low interpatient variability. Conclusions: Continuous oral rucaparib is very well tolerated, with encouraging clinical activity, including objective responses and durable SD, observed during dose-escalation. Once confirmed, the RP2D will be evaluated in platinum-sensitive OC pts with a gBRCA mutation. Clinical trial information: NCT01482715.
A phase I study of oral rucaparib in combination with carboplatin.
Authors: Molife L Rhoda , Roxburgh Patricia , Wilson Richard H. , Gupta Avinash , Middleton Mark R. , Evans T. R. Jeffry , Michie Caroline Ogilvie , Mateo Joaquin , Crawford Donna , Eatock Martin McKinlay , Saka Wasir , Cresti Nicola , Drew Yvette , Giordano Heidi , Despain Darrin , Simpson Dayna , Allen Andrew R. , Jaw-Tsai Sarah S. , Plummer Ruth
Published: March 2020

2586

Background: Targeting poly (ADP-ribose) polymerase (PARP), an enzyme involved in DNA damage repair, may increase efficacy of DNA-damaging agents. This study evaluated the tolerability of oral rucaparib, a potent and selective PARP1/2 inhibitor, in combination with carboplatin (CP). Methods: Patients (pts) aged ≥18 with advanced solid tumors were included. Pts received lead-in doses of IV and oral rucaparib on Days -10 and -5, respectively, followed by CP on Day 1 and oral rucaparib on Days 1-14 q21 days. Treatment continued until disease progression. Pts with benefit could continue on rucaparib monotherapy once CP dosing was completed. Dose escalation was based on toxicities observed in Cycle 1 in cohorts of n=3-6. PK was assessed during Cycle 1. Results: 23 pts (median age 62 yrs [range 20 – 76]; 16 female; 9 ECOG PS=0; 6 ovarian/peritoneal cancer (OC), 5 breast cancer (BC), 2 NSCLC, 10 other tumor) were enrolled. Rucaparib doses of 80, 120, 180, 240, and 360 mg were administered with AUC3 CP, followed by 360 mg rucaparib with AUC4 CP, and currently with AUC5 CP. No DLTs have been reported. Median treatment cycles is 3 (range 1 – 15+). Treatment-related adverse events in ≥4 pts, all grades, include anemia (n=10), fatigue (n=9), nausea (n=7), thrombocytopenia (n=6), constipation (n=5), lethargy (n=5), neutropenia (n=5), and anorexia (n=4). One pt (OC, BRCAwt, AUC3 CP/180 mg rucaparib) had a PR of 5.1 mo duration. Two patients (both with OC; 1 BRCAunk, 1BRCAwt) discontinued CP (after 4 & 8 cycles) and continued on rucaparib monotherapy (additional 5 and 7+ cycles, respectively). An additional 4 pts (all BRCAunk) had stable disease (SD) >12 wks. Overall disease control rate (CR+PR+SD>12 wks) in OC pts across all dose levels was 50% (3/6). Dose-proportional increase in rucaparib exposure was observed with steady state achieved by Day 14 and mean t1/2of 15 h. Oral bioavailability was 38% and dose-independent. Rucaparib exposure was not changed by CP co-administration. Conclusions: The combination of oral rucaparib and CP is well tolerated and exhibits activity at clinically relevant doses of each agent. Further studies in platinum-sensitive and homologous recombination repair deficient populations are warranted. Clinical trial information: NCT01009190.
A randomized, crossover phase I study to assess the effects of formulation and meal consumption on the bioavailability of dovitinib (TKI258).
Authors: Sharma Sunil , Ramanathan Ramesh K. , George Daniel J. , Quinlan Michelle , Kulkarni Swarupa , Homsi Alaeddin , Scott Jeffrey W. , Infante Jeffrey R.
Published: March 2020

2593

Background: Dovitinib (TKI258), an oral multitargeted receptor tyrosine kinase inhibitor, is being studied in a phase 3 trial for renal cell carcinoma. A previous study compared the bioavailability of 2 capsule formulations of dovitinib. Arm 1 of the current study compared relative bioavailability of the final market image (FMI) form (monohydrate tablets) with the clinical service form (CSF; anhydrate capsules) of dovitinib. Arm 2 assessed the effect of food on bioavailability of the FMI tablet in adult patients (pts) with advanced solid tumors. Both arms employed crossover designs. Methods: In arm 1, pts were randomized to receive a single 500-mg dose of dovitinib either as a CSF capsule or FMI tablet, followed by a single 500-mg dose of the other formulation after 7 days of rest. Plasma pharmacokinetic (PK) profiles were determined from blood samples. A linear mixed-effects model fitted to log-transformed PK parameters maximal concentration (Cmax) and area under the curve (AUC0-tlast) was used to determine the relative bioavailability of FMI vs CSF. In Arm 2, pts received 300 mg of the FMI formulation once daily for 22 days after being randomized to 1 of 6 meal sequences with 3 fed or nonfed states (no meal [NM], low-fat [LF] meal, or high-fat [HF] meal) on days 8, 15, and 22. The relative bioavailability of dovitinib under LF and HF vs NM state was determined using the same model as arm 1 for the PK parameters Cmax and AUC0-tlast. Results: The study accrued 21 pts to arm 1 and 42 pts to arm 2. Based on the interim analysis, PK was assessed in 17 evaluable pts in arm 1. The geometric mean ratios (GMRs; 90% CI) for Cmax and AUC0-tlast comparing FMI vs CSF were 0.99 (0.91-1.08) and 0.96 (0.89-1.04), respectively. The FMI formulation was used in arm 2; PK was assessed in 19 pts. Cmax GMR (90% CI) was 0.82 (0.71-0.94) and 0.90 (0.78-1.03) for HF/NM and LF/NM, respectively. AUC0-tlastGMR (90% CI) was 0.91 (0.81-1.02) and 0.99 (0.88-1.10) for HF/NM and LF/NM, respectively. Conclusions: The oral bioavailability of the FMI tablet and CSF capsule were comparable, and there was no clinically relevant effect of food (HF or LF meals) on the bioavailability of the FMI tablet form of dovitinib. Clinical trial information: NCT01155713.
A pharmacogenetic model predicting low paclitaxel clearance based on the DMET platform.
Authors: Nieuweboer Annemieke J.M. , de Graan Anne-Joy M. , Elens Laure , Smid Marcel , Martens John W. M. , Sparreboom Alex , Friberg Lena E. , Elbouazzaoui Samira , Wiemer Erik A.C. , van der Holt Bronno , Verweij Jaap , van Schaik Ron H.N. , Mathijssen Ron H.J.
Published: March 2020

2597

Background: Paclitaxel (PTX) is a commonly used cytotoxic agent. It is metabolized by P450 cytochrome iso-enzymes CYP3A4 and CYP2C8 and has high interindividual variability in pharmacokinetics (PK) and toxicity. Here, we present a genetic prediction model to identify patients with low PTX clearance (CL) using the new Drug-Metabolizing Enzyme and Transporter (DMET; Affymetrix) platform, capable of detecting 1,936 genetic variants (SNPs) in 225 genes. Methods: In a PK study, 270 Caucasian cancer patients were treated with PTX. PK parameters were determined using a limited sampling strategy. HPLC or LC-MS/MS were used to determine PTX plasma concentrations and non-linear mixed effects modelling (NONMEM) was used to estimate individual unbound CL from previously developed PK population models. Subsequently, the cohort of patients was randomly split into a training and validation set. In all patients, the presence of SNPs in metabolic enzymes and transporters was determined using the DMET platform. Selected SNPs were subsequently validated in the validation set. Results: Baseline characteristics were comparable in both sets. The mean CL of the total cohort was 488 ± 149 L/h and the threshold for low CL was set at 339 L/h (1 SD < total mean CL). 14 SNPs were selected to be included in the prediction model and validated in the validation set. For none of these 14 SNPs, evidence for a biological plausible link to taxane metabolism exists. The developed prediction model had a sensitivity of 95% to identify low PTX CL, a positive predictive value of 22% and remained significantly associated with low CL after multivariate analysis correcting for age, gender and Hb levels at start of therapy (P=0.024). Conclusions: This is the first considerably-sized application of the DMET platform to explain PK variability of a widely used anti-cancer drug. Although this validated prediction model for PTX CL had a high sensitivity, its positive predictive value is too low to be of direct clinical use. Likely, genetic variability in DMET genes alone does not sufficiently explain PTX CL, as for example environmental factors may also influence PTX metabolism.
Exposure and clearance of bevacizumab in patients with first-line advanced gastric cancer.
Authors: Sersch Martina A. , Han Kelong , Maia Mauricio , Jin Jin , Allison David
Published: March 2020

2603

Background: Bevacizumab (BEV), rhuMAB VEGF, in combination with chemotherapy (CT) is currently approved in various types of cancer. Recently, BEV+CT was evaluated in 1st line advanced gastric cancer (AGC) in a double-blind randomized phase 3 trial (AVAGAST), but failed to meet the primary OS endpoint (HR=0.87; p=0.1002). BEV pharmacokinetics (PK) is well established by a reference population PK (PPK) model, and BEV PK is consistent across multiple cancer indications. However, BEV PK in AGC was never evaluated. We aimed to assess BEV exposure (EXP) and PK in AGC and to explore the influence of demographic, prognostic and biochemical (DPB) factors. Methods: BEV concentrations (Cp) were measured from plasma samples collected following disease progression from 182 patients (7.5mg/kg Q2W) in AVAGAST. Expected BEV Cp [median and 90% prediction interval (PI)] were simulated using the PPK model and compared to the observed BEV EXP. BEV clearance (CL) in AGC was estimated using NONMEM and compared between subgroups stratified by DPB factors. Results: All DPB factors of AGC are similar to those in other cancers except for lower body weight. No cachexia was observed. BEV Cp was detectable in 162 patients. 85% of observed BEV Cp was below the median BEV Cp simulated using PPK model and 38% below the lower limit of the 90% PI. Median BEV CL in AGC was 4.5 L/day/kg vs. 3 L/day/kg in other cancers. BEV CL was significantly higher (p=0.0012) in patients without prior gastrectomy (4.9 L/day/kg, n=120) than those with gastrectomy (4.1 L/day/kg, n=42). CL appeared to be higher in AGC patients with higher ECOG scores, lower albumin, more metastatic sites, poorer response and later stage AGC. Tumor location (GE Jct vs. Stomach), VEGF-A and ethnicity (Asian vs. Non-Asian) did not correlate with BEV CL. Conclusions: Overall, AGC patients exhibited significantly lower BEV EXP due to a 50% increase in BEV CL vs. other cancers. In addition, BEV is cleared significantly faster in patients without prior gastrectomy. The low BEV EXP in AGC could potentially reduce the effect of BEV in AGC. The underlying mechanism for faster BEV CL in AGC is unknown and warrants further research and potential BEV dose modifications.
Phase I clinical trial of lenalidomide with temsirolimus in patients with advanced cancer.
Authors: Ganesan Prasanth , Piha-Paul Sarina Anne , Naing Aung , Falchook Gerald Steven , Wheler Jennifer J. , Janku Filip , Zinner Ralph , Laday Shell , Kies Merrill S. , Tsimberidou Apostolia Maria
Published: March 2020

2604

Background: Lenalidomide (immunomodulatory and antiangiogenic drug) and temsirolimus (mTOR inhibitor) are potentially synergistic (Raje N, Blood 2004;104(13):4188). We conducted a phase I study of the combination in patients with advanced cancers. Methods: During the escalation phase, lenalidomide (PO days 1-21) and temsirolimus (IV, Q weekly) were given at the following respective doses: level 1 (10 mg, 15mg); level 2 (10 mg, 20 mg); level 3 (20 mg, 20 mg); and level 4 (20 mg, 25 mg) (1 cycle = 28 days). A “3+3” study design was used. The maximum tolerated dose, dose-limiting toxicity, and response were assessed. Results: Forty- three patients were treated (median age: 58 (21-80) years; male/female: 26:17). The most common diagnoses were colorectal cancer (N=5), sarcoma (N=5) and adenoid cystic carcinoma (N=4). Overall, 121 cycles (median: 2) were administered. No dose limiting toxicities were observed. The maximum tested dose (level 4) was used for expansion. Grade 3-4 toxicity (all reversible) occurred in 19 (44%) patients: neutropenia (N=12), thrombocytopenia (N=6), and infection (N=1). Of 43 patients, 31 (72%) received anticoagulation prophylaxis. There were no thrombotic events. Of 36 patients who were evaluable for response, PR was noted in 1 (2.7%), and stable disease (SD) was noted in 17 (47%) patients (SD ≥6 months: 17%). Tumors with SD≥6 months were soft tissue sarcoma, 2/5 (40%), adenoid cystic carcinoma, 1/4 (25%), parotid ca, 1/2 (50%), adrenocortical ca 1/3 (33%), and neuroendocrine ca, 1/4 (25%) (Table). The median progression-free survival was 2.2 months (95% CI, 1.5-2.9) and overall survival was 7.8 months (95% CI, 5.1-10.6). Conclusions: Lenalidomide and temsirolimus combination was well tolerated and had antitumor activity in selected participants with advanced cancer. Clinical trial information: NCT01183663. [Table: see text]
Results of two phase I dose escalation studies of the oral heat shock protein 90 (Hsp90) inhibitor SNX-5422.
Authors: Bauer Todd Michael , Infante Jeffrey R. , Ramanathan Ramesh K. , Weiss Glen , Sachdev Jasgit C. , Burris Howard A. , Hinson James M , Orlemans Everardus O
Published: March 2020

2617

Background: SNX-5422 is a prodrug of SNX-2112, a highly potent, non-geldanamycin analog, HSP90 inhibitor with preclinical anti-tumor activity in multiple tumor models. These phase 1 studies were designed to evaluate safety and tolerability, determine dose limiting toxicities, maximum tolerated doses (MTDs), and describe pharmacokinetics of SNX-2112 and SNX-5422. Methods: Two phase 1, open-label, 3 + 3 dose-escalation studies evaluated SNX-5422 when given daily (QD) or every-other-day (QOD) during the first 30 days of treatment in patients (pts) with advanced solid tumors or lymphoma. Plasma concentrations of SNX-2112 and SNX-5422 were measured after the first and 11th (steady state) doses. Tumor assessments were performed every 8 weeks. Results: In both studies, pts received SNX-5422 QOD, 3 wks on/1 wk off, with doses ranging from 4 to 133 mg/m2 QOD. In one study, pts also received QD doses from 50 to 89 mg/m2, 3 wks on/1 wk off, and 50 mg/m2 QD continuously. Fifty-six pts (34M/22F; mean age 62 years) were enrolled. Treatment-related adverse events were mainly low grade (G), including diarrhea (64%), nausea (39%), vomiting (29%), fatigue (27%), abdominal pain (14%), and anorexia (14%). Reversible G 1 blurry vision, and G 1-2 blurry vision/vision darkening were reported by 1 pt on 100 mg/m2 QOD, and 4 pts treated with 50 to 89 mg/m2 QD. G 3 diarrhea was dose limiting in 2 of 3 pts (89 mg/m2 QD; 133 mg/m2 QOD). MTDs for the QOD and QD schedules were declared at100 mg/m2 and 67 mg/m2, respectively. The QD schedule was associated with higher incidences of treatment related adverse events. 38 pts were evaluable for response including 1 confirmed durable complete response, 1 unconfirmed partial response, and 17 with stable disease. Activity was seen in adrenal, lung, liver, neuroendocrine, GIST, and prostate. All but 2 were seen with the QOD schedule. Conclusions: SNX-5422 mono-therapy was generally well tolerated and showed promising signs of efficacy in pts with advanced solid tumors. Given the superior benefit-risk profile of QOD dosing over QD dosing based on these preliminary clinical findings, 100 mg/m2 QOD has been selected for further clinical testing. Clinical trial information: NCT00506805 and NCT01611623.
Effective incorporation of biospecimen collection for translational studies into a phase III trial: The NeoALTTO experience (BIG 01-06).
Authors: Nuciforo Paolo , Jimenez Jose , Aura Claudia , Fumagalli Debora , Maetens Marion , Prudkin Ludmila , Rothe Francoise , Vazquez Josep , Loi Sherene , Eidtmann Holger , Sotiriou Christos , Baselga Jose
Published: March 2020

3012

Background: Translational research studies in the context of clinical trials using targeted therapies are essential for the identification of biomarkers of response or resistance. However, many challenges (e.g. logistic, technical) can impede proper biological sample collection. The NEOALTTO study provided an excellent opportunity to address these issues. Methods: In this large neoadjuvant phase III multicenter, multinational clinical trial, serial samples (plasma, serum, frozen and FFPE specimens) from patients with breast cancer were collected in 86 sites (23 countries) at several time points (baseline, week 2 and surgery). Standardized operating procedures were made available to sites together with pre-assembled kits for sample collection, processing, storage, and shipment to reduce the variability and increase compliance with the study protocol. All biospecimens were centralized for long term storage. Baseline fresh/frozen samples were processed for downstream analyses according to a pre-defined workflow. Evaluable sample population (ESP) was determined based on the following criteria: tumor cellularity, RNA integrity (RIN), and yield. Results: A total of 12,193 serial samples from 449 of 455 randomized patients was collected. The overall sample missing rate was 9.5% (includes samples not collected by site, withdrawn patients and pCR). Missing rates were 9%, 8%, 13%, and 9% for plasma, serum, frozen and FFPE specimens, respectively. At least 1 frozen tumor tissue was available for 423 (94%), 431 (96%), and 334 (74%) patients at baseline, week 2, and surgery, respectively. After 2 extraction cycles, 629 and 516 baseline frozen samples were processed for RNA and DNA extraction, respectively. The ESP was 71% (58% when RIN considered) and 80% for downstream RNA- and DNA-based analyses, respectively. Incorrect material, inappropriate sample processing and low or absent tumor cellularity were some of the factors affecting the ESP. Conclusions: These results show that careful upfront logistic and technical planning in NEOALTTO had a significant impact on the compliance and the quality of collected material, which may ultimately result in valuable research data. Clinical trial information: NCT00553358.