bluuebunny/crossref_metadata_2025 huggingface dataset:
Alliance A091102: Phase II study of MLN8237 (alisertib) in advanced/metastatic sarcoma.
Authors: Dickson Mark Andrew , Mahoney Michelle R. , Marchello Benjamin T. , Condy Mercedes M. , Tap William D. , Schwartz Gary K.
Published: March 2020

TPS10594

Background: Approximately 13,000 cases of soft tissue and bone are diagnosed annually in the US. Despite primary surgery many patients develop recurrent disease. Response rates to chemotherapy are low and new agents are needed. Gene array studies have shown Aurora Kinase A (AURKA) commonly overexpressed. Inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes. MLN8237 (alisertib) is a novel and oral, ATP-competitive, selective small-molecule inhibitor of AURKA. We hypothesize that alisertib will be an effective treatment for advanced/metastatic sarcoma. Methods: This CTEP-sponsored, investigator-initiated, multi-center phase II study uses alisertib in patients with advanced/metastatic sarcoma and is conducted through the Alliance for Clinical Trials in Oncology (Alliance A091102). Patients must have adequate performance status, organ function, and measurable disease (RECIST v1.1). Patients are enrolled in one of five cohorts, depending on histology: 1) liposarcoma, 2) leiomyosarcoma, 3) undifferentiated sarcoma, 4) malignant peripheral nerve sheath tumor, or 5) other. Patients are treated with alisertib 50mg PO BID d1-d7 every 21 days until either progressive disease or unacceptable toxicity. The primary endpoint is objective overall response rate (ORR). Secondary endpoints include progression-free survival (PFS) and overall survival (OS). Translational objectives include correlation of ORR, PFS and OS with baseline and post-treatment markers of AURKA inhibition in tumor biopsies and baseline and post-treatment [F-18] FLT-PET scans. A Simon two-stage design is used for each of the 5 cohorts and one confirmed response in the first 9 patients expands enrollment in that cohort to 24. Enrollment began in December 2012. As of January 2013, 14 pts have been enrolled. Funded by the Alliance for Clinical Trials in Oncology. Clinical trial information: NCT01653028.
Phase I/II study of the safety, pharmacokinetics, and efficacy of pomalidomide in the treatment of Kaposi sarcoma in individuals with or without HIV.
Authors: Polizzotto Mark Niccolo , Uldrick Thomas S. , Wyvill Kathleen , Aleman Karen , Sereti Irini , Tosato Giovanna , Whitby Denise , Bevans Margaret , Maldarelli Frank , Figg William Douglas , Steinberg Seth M. , Yarchoan Robert
Published: March 2020

TPS10595

Background: Kaposi sarcoma (KS) is a multicentric angioproliferative tumor seen most frequently in people with HIV. It is caused by the gammaherpesvirus Kaposi-sarcoma associated herpesvirus (KSHV, or human herpesvirus 8) and is remarkable for its tendency to progress or regress based on host immune factors. Pomalidomide is an orally available third generation thalidomide derivative with immunomodulatory and antiangiogenic properties that may address unmet clinical needs in KS. Methods: The primary objective is to assess the safety, tolerability and pharmacokinetics of pomalidomide in subjects with KS, whether HIV associated or not, and to explore its antitumor effect at the tolerable dose once determined. This is the first assessment of this agent in patients with HIV and/or KS. Subjects with confirmed KS and no symptomatic pulmonary or visceral KS are eligible. Those with HIV must be compliant with HAART; have achieved an HIV viral load <10,000 copies/mL; and in the phase II portion have KS increasing despite HAART and HIV suppression for ≥2months, or stable despite HAART for ≥3months. In the phase I portion, up to 6 subjects will be treated with pomalidomide 5mg orally daily for 21 days of a 28 day cycle. Subject to evaluation of adverse events and tolerability, this may be deescalated to 3mg orally daily 21 of 28 days in a second cohort of up to 6 subjects. If either dose proves tolerable, the study will proceed to the phase II portion, and enroll up to 15 HIV positive and 10 HIV negative subjects. Antitumor activity will be assessed using modified ACTG KS response criteria in parallel with quality of life assessment. Key correlative studies include evaluation of immune responses including T cell numbers and activation in peripheral blood and tumor tissue and KSHV specific T-cell responses; HIV and KSHV activity and associated cytokines; and the first exploration of effects of pomalidomide pharmacokinetics when administered with common antiretroviral agents. Progress: The study opened to accrual in January 2012. The phase I portion is complete with no DLTs at the dose of 5mg 21 of 28 days. Phase II has accrued 11 subjects (4 HIV negative, 7 HIV positive) at this dose. Clinical trial information: NCT01495598.
Identification and validation of an assay predictive of response and prognosis following anthracycline-based chemotherapy for early breast cancer.
Authors: Mulligan Jude M. , Hill Laura A. , Deharo Steve , Keating Katherine E. , Raji Olaide , McDyer Fionnuala A. , James Jacqueline , Irwin Gareth , Boyle David , Quinn Jennifer E. , Mullan Paul B. , James Colin R. , Salto-Tellez Manuel , Davison Timothy S. , Johnston Patrick , Couch Fergus J. , Harkin D. Paul , Kennedy Richard D.
Published: March 2020

TPS11120

Background: Currently there is no biomarker to predict specific benefit from DNA-damaging anthracycline and cyclophosphamide-based chemotherapy in the clinic. Loss of the Fanconi anemia/BRCA (FA/BRCA) DNA-damage response pathway occurs in approximately 25% of breast cancer and results in sensitivity to DNA-damaging agents. We therefore developed an assay to detect loss of the FA/BRCA pathway, for the purpose of predicting benefit from chemotherapy. Methods: 21 FA patient samples were analyzed to identify genetic processes associated with loss of the FA/BRCA pathway. Unsupervised hierarchical clustering was then performed using 60 BRCA1/2 mutant and 47 sporadic tumor samples and a molecular subgroup was identified that was defined by the molecular processes representing loss of the FA/BRCA pathway. A 44-gene DNA Damage response deficient (DDRD) assay was developed that could identify this subgroup from formalin fixed, paraffin embedded (FFPE) samples in the clinic. Results: In a publicly available independent cohort of 204 patients, the assay predicted response to neoadjuvant DNA-damaging chemotherapy (5-fluorouracil, anthracycline and cyclophosphamide) with an odds ratio of 4.01, (95% Cl:1.69-9.54). We also analysed samples from an independent cohort of 114 node-negative breast cancer patients treated with adjuvant 5-fluorouracil, epirubicin and cyclophosphamide treatment at the Northern Ireland Cancer Centre. The DDRD assay significantly predicted 5-year relapse free survival with a hazard ratio of 0.27 (95% Cl:0.10-0.83). The assay was not predictive of survival in patients who did not receive chemotherapy. Conclusions: An FFPE tissue-based assay that detects loss of the FA/BRCA pathway has been developed and independently validated as a predictor of response and prognosis following DNA damaging anthracycline/cyclophosphamide-based chemotherapy in the neoadjuvant and adjuvant settings.
Correlation of 64Cu-DOTA-trastuzumab positron emission tomography (PET) imaging with HER2 status by immunohistochemistry (IHC).
Authors: Mortimer Joanne E. , Park Jinha Mark , Carroll Mary I. , Poku Kofi , Miles Joshua , Colcher David , Raubitschek Andrew Antony , Tran Tri , Bading James R.
Published: March 2020

TPS11121

Background: We have developed 64Cu-DOTA-trastuzumab for PET imaging of HER2-positive breast cancer. We have determined that administering trastuzumab (45 mg) prior to 64Cu-DOTA-trastuzumab sharply reduces liver uptake of the radiotracer. We are now testing whether tumor uptake of 64Cu-DOTA-trastuzumab correlates with variable IHC staining in women with advanced breast cancer. Methods: Eligibility criteria included biopsy confirmation of metastatic disease that was HER2 1+, 2+, or 3+ by IHC, no anti-HER therapy within the prior 4 mo, and at least 1 non-hepatic site of metastasis > 20 mm outside the biopsy site. Staging workup included 18F-FDG PET-CT. Patients received 45 mg of cold trastuzumab prior to 64Cu-DOTA-trastuzumab. PET-CT scans were obtained at 21-25 h (Day 1) and 47-48 h (Day 2) over axial fields of view chosen in reference to 18F-FDG. Uptake in prominent lesions was measured in terms of maximum single-voxel SUV (SUVmax). Lesions identified on CT and judged to have image intensity > adjacent tissue by an expert radiologist were considered positive on PET. Results: Fourteen women (median age 56, range 35-75 y) have undergone imaging. HER2 status by IHC was 3+ in 9 pts., 2+ in 5 and 1+ in 1. Two women with IHC 2+ disease were FISH+. In the patients considered clinically HER2 positive (IHC 3+ or 2+, FISH+), 64Cu-DOTA-trastuzumab sensitivity was 75 and 90%, respectively, on Days 1 and 2, compared with 94% for 18F-FDG. Tumor uptake of 64Cu-DOTA-trastuzumab was also readily visualized in HER2-negative patients (measured detection sensitivity 90%). There were no false positive findings with 64Cu-DOTA-trastuzumab. Lesion uptake of 64Cu-DOTA-trastuzumab was higher in HER2+ than in HER2- patients (SUVmaxmean ± sem: Day 1 8.9±0.6 vs 4.3±0.2; Day 2 9.9±0.8 vs 5.4±0.3, p < 0.001). Conclusions:64Cu-DOTA-trastuzumab PET visualizes HER2 1+, 2+ and 3+ metastatic breast cancer with high sensitivity and specificity. Tumor uptake of 64Cu-DOTA-trastuzumab-PET in IHC 1+ and 2+ patients implies possible benefit from anti-HER2 therapies for individuals whose cancers are currently considered HER2 negative. Research Support: DOD1024511. Clinical trial information: NCT01093612.
NSABP B-47: A randomized phase III trial of adjuvant therapy comparing chemotherapy alone to chemotherapy plus trastuzumab in women with node-positive or high-risk node-negative HER2-low invasive breast cancer.
Authors: Fehrenbacher Louis , Jeong Jong-Hyeon , Rastogi Priya , Geyer Charles E. , Paik Soonmyung , Ganz Patricia A. , Land Stephanie R. , Costantino Joseph P. , Swain Sandra M. , Mamounas Eleftherios P. , Wolmark Norman
Published: March 2020

TPS1139

Background: Adjuvant trastuzumab trials in HER2+ breast cancer (BC) demonstrated a large reduction in recurrence and death. Central testing showed HER2 non-amplified participants derived similar benefit. Among HER2-amplified patients (pts), multiple studies showed no effect on benefit by degree of amplification. Blinded internal and external review confirmed the non-amplified nature of the HER2 normal group. Based on these findings, NSABP B-47, sponsored by the NCI, was activated January 2011 and is actively accruing. The study is NCI central IRB approved, open via the CTSU, and endorsed by SWOG, ECOG, and RTOG. Methods: Study: Chemotherapy treatment is by physician choice: The non-anthracycline regimen is TC (docetaxel 75 mg/m2, cyclophosphamide (C) 600 mg/m2) IV q 3 wks for 6 cycles; the anthracycline regimen is AC → WP (doxorubicin 60 mg/m2 and C 600 mg/m2 IV either q 3 wks or q 2 wks [investigator discretion] for 4 cycles → paclitaxel 80 mg/m2 IV wkly for 12 doses). Pts are randomly assigned to chemotherapy with or without trastuzumab for 1 year. Pts receive adjuvant radiation therapy and endocrine therapy, as clinically indicated. Detailed menstrual history, concurrent medications, weight changes, and biomarkers (estrogen, stress, inflammation), are being collected. Eligibility: Eligibility includes: node positive or high risk node negative BC pts; HER2 IHC 1+ or 2+ scores, but non amplified by FISH; normal cardiac, renal, and liver function. Detailed eligibility will be provided. Statistical Design: The primary aim is to determine whether the addition of trastuzumab to chemotherapy improves invasive disease-free survival (IDFS). 3,260 pts will be enrolled to provide statistical power of 0.9 to detect a 33% reduction in the hazard rate of IDFS using a one-sided alpha level of 0.025. Progress: Protocol was activated in January 2011. First pt was entered in February 2011. As of January 23, 2013, 1,416 of 3,260 (43.4 %) pts have been enrolled. Updated information on enrollment and study background will be provided. Support: NCI U10-12027, -37377, 69651, 69974, and Genentech, Inc. Clinical trial information: NCT01275677.
A randomized phase III trial comparing nanoparticle-based paclitaxel with solvent-based paclitaxel as part of neoadjuvant chemotherapy for patients with early breast cancer (GeparSepto): GBG 69.
Authors: Jackisch Christian , Wiebringhaus Frank , Conrad Bettina , Weigel Michael , Aktas Bahriye , Wagner Harald , Latos Kunibert , Kohls Andreas , Bueckner Ute , Hauzenberger Tanja , Bangemann Nikola , Hackmann John , Clemens Michael R. , Heinrich Bernhard , Tome Oliver , Loibl Sibylle , Nekljudova Valentina , Von Minckwitz Gunter ,   German Breast Group
Published: March 2020

TPS1141

Background: Anthracyclines (A) followed by taxanes (T) are standard of care for neoadjuvant therapy in breast cancer (BC). A reverse sequence of T followed by A was suggested to achieve higher pCR rates. Previous studies have shown that dual anti-HER2 blockade is superior to trastuzumab (H) alone and thus can increase the pCR rate by 20%. Nab-paclitaxel (nP) is a solvent-free formulation of P encapsulated in albumin and might also improve the pCR rate with eventually lower toxicity. Methods: The GeparSepto study (NCT01583426) will randomize 1200 patients to either nP (150 mg/m²) q1w or P (80mg/m²) q1w for 12 weeks followed by 4 cycles conventionally dosed EC (E 90mg/m², C 600 mg/m²) q3w for 4 cycles. Primary objective is to compare the pCR rate (ypT0+ ypN0). Patients with untreated, histologically confirmed cT2- cT4d BC can be included. HER2+ patients receive H (loading dose 8mg/kg; 6 mg/kg) plus pertuzumab (loading dose 840 mg; 420 mg) q3w concomitantly. Biomaterial including FFPE from core biopsy, serum, plasma and full blood is collected. HER2, ER, PgR, Ki67 and SPARC status will be centrally assessed prior to randomization for stratification. P was assumed to achieve a pCR rate of 33% which will be increased to 41% when using nP, corresponding to an odds ratio of 1.41. To investigate resistance to anti-HER2 treatment, patients with HER2+ BC are randomized prior to start of chemotherapy to receive either 6 weeks H, pertuzumab or the combination as biological window with biomaterial collection prior to start of therapy and after week 6 prior to start of chemotherapy. Results: After been approved by ethics committees and authorities recruitment started in 7/2012 in 56 sites. 293 patients were recruited (53 HER2+; 240 HER2-) by 1st Feb 2013. A first safety interim analysis is planned after 60 patients have finished therapy. Conclusions: GeparSepto investigates the efficacy of neoadjuvant nP compared to solvent-based P given weekly with a dual blockade of the HER2 receptor in HER2-pos BC. Interim safety results for nP will be presented. The window-substudy is funded within the EU-FP7 project RESPONSIFY No 278659. Clinical trial information: NCT01583426.
Phase I/II dose-escalation study of VB-111, an antiangiogenic gene therapy, in patients with recurrent glioblastoma multiforme.
Authors: Brenner Andrew Jacob , Cohen Yael , Vredenburgh James J , Peters Katherine B. , Breitbart Eyal , Bangio Livnat , Sher Naamit , Harats Dror , Wen Patrick Y.
Published: March 2020

TPS2102

Background: VB-111 is an anti-angiogenic agent consisting of a non-replicating adenovirus vector (Ad-5) with a modified murine pre-proendothelin promoter leading to apoptosis of tumor vasculature by expressing a fas-chimera transgene in angiogenic endothelial cells. In a phase I/II dose-escalation study, safety and efficacy of VB-111 in patients with recurrent Glioblastoma Multiforme (GBM) were evaluated. Methods: VB-111 was administered as a single intravenous infusion at escalating doses from 1x1012 to 3x1012 viral particles (VPs), followed by repeat doses of 3x1012 or 1x1013every 2 months. Assessments included safety, pharmacokinetics, tumor response (RANO criteria) and overall survival (OS). Results: Twenty eight patients aged 26 – 74 years at 3 medical centers in the US received up to 8 repeat doses of VB-111. The median OS was 360 [range: 70-574] and 266 days [range: 28-664] for patients receiving at least one dose of 1x1013VPs (high dose) vs. subjects who received lower doses, respectively (p NS). Progression free survival was 87 vs 55 days for patients who received high dose and for lower doses, respectively (p = 0.01). Median follow-up was 232 days. Three patients had a partial response (PR) at 82, 86 and 408 days post initial VB-111 dosing. Twenty one of the patients who progressed on VB-111 treatment received bevacizumab off study; 7 of the 15 evaluable patients (47%) had a PR compared to 30% expected according to literature. VB-111 was safe and well tolerated, 53 adverse events were reported, 14 were classified as possibly related to VB-111. All events were of CTCAE grade 1-2 except one grade 3 pulmonary embolism. There were no study related deaths. One patient developed peri-tumoral edema, which resolved with corticosteroid therapy. Events occurring in > 10% of the patients included headache and fatigue. Conclusions: VB-111 was safe and well tolerated in patients with recurrent GBM with repeat doses of up to 1x1013 VPs. Tumor responses were seen. Overall survival was about 3 months longer than historical data in recurrent GBM, including standard of care anti-angiogenic agents. Data suggests that VB-111 potentiates the response to bevacizumab given at further progression. Clinical trial information: NCT01260506.
Dose-intensified rechallenge with temozolomide: One week on/one week off versus 3 weeks on/one week off in patients with progressive or recurrent glioblastoma (DIRECTOR).
Authors: Tabatabai Ghazaleh , Wick Wolfgang , Reifenberger Guido , Steinbach Joachim Peter , Schnell Oliver , Hau Peter , Herrlinger Ulrich , Sabel Michael , Ketter Ralf , Schlegel Uwe S. , Marosi Christine , Goldbrunner Roland , Homicsko Krisztian , Nikkhah Guido , Pichler Josef , Vajkoczy Peter , Meixensberger Juergen , Weller Michael
Published: March 2020

TPS2103

Background: No standard of care has been defined for patients with glioblastoma who relapse or progress on or after standard temozolomide (TMZ)-based radiochemotherapy. Rechallenge with TMZ using various dose-intensified regimens is a common approach for recurrent glioblastoma. O6-methylguanylmethyltransferase (MGMT) promoter methylation is a strong prognostic marker in newly diagnosed glioblastoma. However, in recurrent glioblastoma, the prognostic value of the MGMT status has remained unclear. Methods: The DIRECTOR trial is an open-label prospectively randomized phase II trial investigating 2 different TMZ rechallenge regimens, i.e. 1 week on/1 week off (Arm A, 120-150 mg/m2 per day for 7 days) versus 3 weeks on/1 week off (Arm B, 80-100 mg/m2 per day for 21 days) in recurrent glioblastoma. Patients were enrolled at first progression after having completed the first-line TMZ radiochemotherapy and at least 2 adjuvant TMZ cycles. At randomization, MGMT gene promoter methylation status from the primary or recurrent tumor was mandatory. The study treatment was monitored every 2 months by MRI using MacDonald criteria. Translational studies included blood biomarker (e.g. regulatory T cell counts, MGMT activity in peripheral blood). In addition, quality-of-life was evaluated by QLQ-C30 and QLQ-BN20 EORTC scores. Neurocognitive testing using the NeuroCogFx was optional. The primary endpoint is median time-to-treatment failure that was defined as progression, toxicity or death from any cause. Secondary endpoints are progression-free survival, overall survival, response and MGMT correlations. The trial was performed in 16 sites in Austria, Germany, and Switzerland. 105 of 166 patients have been enrolled (53 patients in Arm A and 52 patients in Arm B) before the enrollment was prematurely stopped on 30 June 2012. The database will be closed on 30 June 2013. Clinical trial information: NCT00941460.
Phase II trial of triple-receptor tyrosine kinase receptor inhibitor nintedanib (BIBF 1120) in recurrent high-grade gliomas.
Authors: Norden Andrew David , Schiff David , Ahluwalia Manmeet Singh , Lesser Glenn Jay , Nayak Lakshmi , Lee Eudocia Quant , Muzikansky Alona , Dietrich Jorg , Smith Katrina H. , Gaffey Sarah C. , McCluskey Christine Sceppa , Ligon Keith L. , Reardon David A. , Wen Patrick Y.
Published: March 2020

TPS2104

Background: Bevacizumab is the standard of care for patients with recurrent high-grade glioma (HGG). However, with current treatment options the median duration of response is only approximately 4 months. Potential mechanisms of resistance include upregulation of fibroblast growth factor (FGF) and increased pericyte coverage mediated by platelet-derived growth factor (PDGF). Nintedanibis an oral, small-molecule tyrosine kinase inhibitor of PDGFR α/β, FGFR 1/3, and vascular endothelial growth factor receptor (VEGFR) 1-3 that may overcome the problem of resistance to prior anti-VEGF therapy. Methods: This is an open-label, phase II trial in adults with first or second recurrence of HGG, stratified by prior therapy with bevacizumab. The primary endpoint is 6-month progression-free survival (PFS6) in the bevacizumab-naive arm and PFS3 in the post-bevacizumab arm. A Simon two-stage design is employed. Although the glioblastoma (GBM) comparison is the one of primary concern, 10 anaplastic glioma (AG) participants will be accrued to each arm in exploratory cohorts. Results: Nine of 40 GBM patients and 10 of 10 AG patients have been accrued in the bevacizumab-naive arm. Data in this arm are maturing. In the post-bevacizumab arm, 14 patients have been accrued, 10 of whom had GBM (71%). There were 11 men (79%), median age was 52 years (range 32-70), and median KPS was 90 (range, 60-100). One patient with anaplastic astrocytoma was not evaluable for response analysis because of early withdrawal of consent. There have been no responses. Two patients (1 with GBM and 1 with anaplastic oligodendroglioma) achieved stable disease. Median PFS was 28 days (95% CI: 27-28), and maximum PFS was 56 days. Median OS was 57 days (95% CI: 29-155). The post-bevacizumab arm was stopped after stage 1. Treatment was well tolerated, with limited Grade 3 liver function test abnormalities (n = 3), abdominal pain (n = 1), and hypertension (n = 1). Grade 1-2 adverse events also included diarrhea, nausea/vomiting, fatigue, and bleeding. Conclusions: Despite limited toxicity, nintedanibis ineffective in the cohort of recurrent HGG patients who failed bevacizumab. Updated results in the bevacizumab-naive arm will be presented. Clinical trial information: NCT01380782.
A phase Ib study of combined angiogenesis blockade with REGN910 (SAR307746), a selective monoclonal antibody (MAb) against angiopoietin-2 (Ang2) and ziv-aflibercept in patients with advanced solid tumor malignancies.
Authors: Adriaens Lieve , Papadopoulos Kyriakos P. , Graham Donna M. , Patnaik Amita , Razak Albiruni R.A. , Tolcher Anthony W. , Siu Lillian L. , Rasco Drew Warren , Trail Pamela , Brownstein Carrie M. , Lowy Israel
Published: March 2020

TPS2618

Background: REGN910 is a selective, fully human Angiopoietin-2 (ANG-2) MAb, which potently blocks signaling through the Tie2 receptor. Ziv-aflibercept (ZAFL) is a recombinant human fusion protein that acts as a decoy receptor for vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PlGF), thereby preventing the interaction of these ligands with their receptors. In several mouse xenograft models, combination of the 2 anti-angiogenic compounds, REGN910 and ZAFL, demonstrated significantly enhanced tumor growth inhibition relative to either agent alone, suggesting that dual angiogenic blockade is worth exploring in cancer patients. Methods: This phase 1b study employs a standard 3+3 dose escalation design exploring 5 different combination treatment dose levels of REGN910 and ZAFL. Once the recommended phase 2 dose (RD) of the combination treatment is determined, additional patients will be enrolled in a safety expansion cohort, for a planned total enrollment of up to 40 patients. The primary study objectives are to evaluate the safety and determine the RD of the 2 drugs in combination when both are administered IV every 2 weeks in patients with advanced solid tumors. Secondary endpoints include characterization of the PK and potential immunogenicity of REGN910 and ZAFL when given in combination, evaluation of correlative PD biomarkers related to REGN910 and ZAFL, and identification of antitumor activity. Enrollment to cohorts 1 and 2 has been completed without DLT. Enrollment to cohort 3 opened in December 2012. Updated enrollment status will be presented. Reference: ClinicalTrials.gov Identifier: NCT01688960. Clinical trial information: NCT01688960.
Phase I study of pazopanib (PAZ) in combination with PCI-24781 (PCI) in patients (pts) with metastatic solid tumors with new tumor proliferation imaging correlates in renal cell carcinoma (RCC) and sarcoma.
Authors: Truong Thach-Giao , Grabowsky Jennifer A. , Chen Stephanie , Ea Roth , Ko Andrew H. , Friedlander Terence W. , Bergsland Emily K. , Harzstark Andrea Lynne , Reinert Anne , Fung Gordon , Daud Adil , Munster Pamela N.
Published: March 2020

TPS2623

Background: PAZ is a multi-targeted tyrosine kinase inhibitor of VEGFR, PDGFR, and C-KIT, approved for metastatic RCC and refractory sarcoma based on phase III data showing prolonged PFS (JCO 2010;28:1061-8 and Lancet 2012;379:1879-86). PCI is a potent pan-HDAC inhibitor (pan-HDACi), observed in cell lines to change regulation of genes involved in cell signaling, apoptosis, proliferation, differentiation, and angiogenesis (Anticancer Res 2011;31:1115-23). Pre-clinical models suggest epigenetic modification with an HDACi potentiates PAZ’s efficacy by causing chromatin instability and gene expression changes involved in drug resistance (Can Res 2005;65:3815-22 and BJC 2009;100:758-63). We therefore designed a Phase Ia/b clinical trial combining PCI with PAZ in pts with advanced solid tumors, with an expansion cohort for preliminary efficacy in RCC and sarcoma. Methods: Primary objective of this phase Ia/b study is to evaluate the safety and tolerability of the combination of PAZ and PCI to determine the MTD and RP2D. In phase Ia, we utilized an accelerated phase I design. The phase Ib portion will include up to 20 pts per expansion cohort, for up to 32-70 pts enrolled. In phase 1a, pts receive run-in PCI alone on C1D-7 to D-4. Starting with C1D1, pts receive oral PCI on D1-5, 8-12, 15-19 BID 4 hrs apart and PAZ daily (D1-28) q28D cycle. CORRELATIVES: Pre- and post-treatment (Tx) H3 & H4 acetylation and HDAC activity in PBMCs. In phase Ib, these will also be studied in tumor biopsies. We will measure expression of VEGF, VEGFR, RAD51, HIF, Ki67; and analyze SNPs through genomic profiling. We will correlate response with pre- and post-Tx tumor thymidine uptake using 18F-fluorothymidine (FLT-PET) PET. Current Status: This is the 1st trial exploring the combination of an HDACi with PAZ in RCC and sarcoma, where there is an unmet need for new tolerable therapies. It will study FLT-PET, an imaging correlate that captures tumor proliferation and may have a role as a predictive biomarker. We are currently in phase Ia. Enrollment in the 3rd cohort exploring higher doses of PAZ will begin in Feb 2013. Clinical trial information: NCT01543763.
Evesor: The first phase I trial combining multiple dose/dosing schedules—Pharmacodynamic assessments and mathematical modeling to optimize the benefit/toxicity ratio of everolimus and sorafenib association.
Authors: You Benoit , Freyer Gilles , Tod Michel , Rodriguez Claire , Cassier Philippe Alexandre , Hommel-Fontaine Juliette , Valette Pierre-Jean , Guitton Jerome , Henin Emilie
Published: March 2020

TPS2625

Background: In 2004, FDA declared the abandon rate of new oncology drugs was too high and new trial designs should be developed. The combination of everolimus (EVE) and sorafenib (SOR) is rational, and has been studied in 11 phase I studies, where approved monotherapy regimens have been used (EVE qd and SOR bid). Although promising efficacy outcomes were found, the combination may be abandoned due to metabolical and skin toxicity. The best doses and dosing schedules of EVE and SOR associated with the optimal benefit/toxicity ratio may be identified using mathematical modeling of data from an adequately designed multiparameter trial. Methods: This academic study is composed of 4 arms with different dosing schedules of EVE and SOR (qd; 1 week/2; 3 days-on …), and dose escalations. Patients with different tumor types potentially sensitive to the combination are enrolled. Multiparameter assessments include: pharmacokinetics (PK); pharmacodynamics (PD) with control of signaling pathway inhibition (ERK, AKT, S6K) in 2 tumor biopsies & repetitive PBMC assays; kinetics of circulating tumor DNA kinetics & angiogenesis markers; tumor angiogenesis changes using repeated DCE-ultrasounds; and radiological/clinical effects. These data enrich a translational multiscale model meant to quantify the relationships between drug dosing modalities, PK, PD, radiological and clinical effects, developed in parallel. The doses and dosing schedules of EVE and SOR which enable maximization of benefit/toxicity ratio (utility function) will be searched using simulations, and then tested. The protocol was approved by ethic committee in 2012. Two patients a month have been enrolled in 2 centers since January 2013. Expected results: Mathematical modeling of the relationships between dosing modalities; PK; PD; radiological and clinical effects based on the data from an adequately designed trial may help determine the optimal doses and dosing schedules of EVE and SOR (with the best benefit/toxicity ratio), and avoid the combination abandon. EVESOR study may embody the proof of concept of this new model-based trial design. Clinical trial information: 2012-002818-39.
Phase I dose escalation study of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with advanced hepatocellular carcinoma (HCC) with or without chronic viral hepatitis.
Authors: Sangro Bruno , Crocenzi Todd S. , Welling Theodore Hobart , Iñarrairaegui Mercedes , Prieto Jesús , Fuertes Carmen , Delanty Laurie , Feely William , Anderson Jeffrey , Grasela Dennis M. , Wigginton Jon M. , Gupta Ashok Kumar , Melero Ignacio
Published: March 2020

TPS3111

Background: Pts with advanced HCC have limited treatment options. Sorafenib, the current standard of care, achieves only modest overall survival improvements. There is a clear etiologic association between HCC and prior/concurrent hepatitis B (HBV) or C (HCV) infection. Programmed death-1 (PD-1) is an immune checkpoint receptor that inhibits T-cell activation when bound by ligands including PD-L1/L2. PD-L1 overexpression has been noted on HCC tumors, and PD-1/PD-L1 interaction may contribute to viral hepatitis induced T-cell exhaustion. Nivolumab, a PD-1 receptor blocking antibody, has shown efficacy against various solid tumor types in Ph 1 trials. We hypothesized that blockade of PD-1/PD-L1 interaction could enhance T-cell activation and mediate antitumor and/or antiviral activity in HCC pts. We describe a phase I, dose-escalation study of nivolumab in advanced HCC pts. Methods: Successive pt cohorts with histologically confirmed advanced HCC with/without HBV or HCV infection (N=72 max) will be treated on 3 distinct arms with IV nivolumab at 0.3, 1 and 3.0 mg/kg (uninfected or HCV-infected pts) or 0.1, 0.3, 1 and 3.0 mg/kg (HBV-infected pts) every 2 weeks using a 3+3 escalation scheme. Pts must have progressive disease or intolerance after ≥1 line of therapy or have refused sorafenib treatment, and a Child-Pugh class A. HBV-infected pts must be receiving antiviral therapy (viral DNA <100 IU/mL) for ≥3 months. Pts with brain metastasis, encephalopathy, prior/current ascites requiring paracentesis, history of recent variceal bleeding, active coinfection with HIV, or both HBV and HCV, or concurrent hepatitis D and HBV infection will be excluded. Primary endpoints include characterization of safety, tolerability, dose-limiting toxicities and maximum tolerated dose of nivolumab. Secondary endpoints include assessment of the preliminary antitumor activity (per modified RECIST for HCC), PK and immunogenicity. Exploratory endpoints include evaluation of the relationship between tumor PD-L1 expression and clinical outcome, and nivolumab’s antiviral and immunoregulatory activity in peripheral blood and/or tumor specimens. Clinical trial information: NCT01658878.
A phase I/II study of multiple peptides cocktail vaccine for advanced/recurrent ovarian cancer.
Authors: Takeuchi Satoshi , Shoji Tadahiro , Kagabu Masahiro , Honda Tatsuya , Miura Fumiharu , Omi Hideo , Takada Anna , Sugiyama Toru
Published: March 2020

TPS3116

Background: Despite improvement in chemotherapy including the molecular targeting agents, advanced or recurrent ovarian cancer (A/ROC) are still incurable. Some tumor associated proteins, hypoxia-inducible protein 2 (HIG2), and tumor related vascular endothelial growth factor receptor 1,2 (VEGFR1,VEGFR2) were found to be candidates as new targets, and their epitope peptides have been shown to have the ability to induce specific cytotoxic T lymphocyte ( CTL) responses. We conducted a phase I/II study of these peptides cocktail vaccine (PCV) in patients with A/ROC in order to evaluate toxicity, immunological response, and tumor response. Methods: 23 patients positive for human leukocyte antigen (HLA)-A2402 (A24) and 15 patients with HLA-A0201(A02) were enrolled in this study. Enrollment is still on going up to 30 evaluable patients in each group. PCV for A24 comprises FOXM1(Forkhead Box M1), MELK(maternal embryonic leucine zipper kinase), HJURP(Holliday junction recognition protein), VEGFR1 and VEGFR2. As for A02- PCV comprises HIG2, VEGFR1and VEGFR2. Cocktails were made at a dose of 1mg of each peptide with GMP grade-adjuvant, MONTANIDE ISA51. Vaccination schedule included weekly subcutaneous administration for first 12 weeks, then bi-weekly administration for next 16 weeks, then further vaccination was done monthly for 8 times and 3-6 months as a maintenance step according to patient’s need. Pre- and post-vaccination blood samples were obtained from the patients for toxicity assessment and immunological evaluation. Clinical responses were evaluated every three months by RECIST v 1.1. Results: PCV were generally well tolerated with no major adverse events, and most of the patients developed specific CTL responses. One patient showed complete response, two showed partial response and 10 showed stable disease in 22 evaluable patients. At the time of the analysis, median overall survival was 5 months (from 30 to 623 days) and 9 months(from 54 to 921 days),in A24 and A02, respectively. 11 patients remained alive with median follow up of 9 months. Conclusions: These findings suggest these peptides cocktail vaccines are safe and applicable for advanced/recurrent ovarian cancer. Clinical trial information: UMIN000003862, UMIN000003860.
Results of the CARMA study to investigate catumaxomab therapy for ascites related to peritoneal carcinomatosis in clinical practice.
Authors: Kurbacher Christian M. , Sehouli Jalid , Welslau Manfred , Tempelhoff G.-F. , Kufahl J. , Marth Christian , Oettle Helmut , Schmalfeldt Barbara , Urban Elisabeth , Kunzmann Volker
Published: March 2020

TPS3119^

Background: The trifunctional antibody CATU (catumaxomab) is approved in the EU for intraperitoneal (IP) treatment of malignant ascites (MA) in patients (pts) with EpCAM-positive carcinomas. Clinical data for CATU are based on 2 phase III and several phase I/II trials. However, the routine use of CATU has not been evaluated systematically. Therefore, a prospective observational study (CARMA) was started in 2010 investigating the administration of CATU in a total of 160 pts with MA under routine conditions. Participating centers were hospitals and oncologic practices in Germany and Austria. Hereby, we report on the results of the 2nd interim CARMA analysis. Methods: This analysis included 103 pts with MA due to EpCAM-positive carcinomas: ovarian, n=37; gastric, n=13; pancreatic, n=10; colorectal, n=6, miscellaneous, n=37. Pts were treated with CATU at a routine setting at 4 increasing dosages over a 2-week interval. The primary endpoint was puncture-free interval (PFI), secondary endpoints included safety and overall survival (OS). Results: The study population mainly comprised pts with advanced-stage disease. In 65% distant metastases were present. Therapy was given in 24 hospitals (73 %) and 9 outpatient facilities (27 %). Pts suffered from typical MA related symptoms such as abdominal swelling (77%), pain (56%), dyspnea (27%), anorexia (31%), constipation (13%). In 67 pts (65%), CATU was given as planned, 36 pts (35%) received <4 infusions. Most frequent adverse events (AE) were fever (20%), nausea (14%) and diarrhea (6%).The median PFI was 57 days (d), the median OS was 100 d. For the subgroups ovar/non-ovar, a median PFI of 93/41 d and a median OS of 115/72 d was observed. Conclusion: CARMA represents the first systematic evaluation of CATU therapy given for MA under routine conditions. In accordance to previous prospective trials, the presented 2nd interim-analysis was able to demonstrate a clinically meaningful benefit of CATU, particularly impressive in ovarian cancer pts. CATU showed an acceptable safety profile, thus allowing for treatment at an outpatient setting in an adequately selected group of pts. The final CARMA analysis after including 160 pts is thus eagerly awaited. Clinical trial information: DRKS00000458.
A multipeptide vaccine plus toll-like receptor agonists in melanoma patients, with evaluation of the vaccine site microenvironment and sentinel immunized node (Mel58; NCT01585350).
Authors: Slingluff Craig L. , Petroni Gina R. , Chianese-Bullock Kimberly A. , Grosh William W. , Weiss Geoffrey R.
Published: March 2020

TPS3125

Background: Recent data show clinical activity of cancer vaccines containing a defined cancer antigen, and a peptide vaccine for melanoma. However, immune responses to peptide vaccines are often transient and of low magnitude. The most common adjuvant for peptide vaccines for melanoma has been an incomplete Freund’s adjuvant (IFA), which may have suboptimal adjuvant properties. Toll-like receptor (TLR) agonists offer the potential to improve the magnitude and persistence of antitumor T cell responses, either in combination with IFA or alone. CD40 ligation at the vaccine site microenvironment (VSME) may also improve adjuvant activity of TLR agonists and may be provided by CD4 T cell activation. We report a clinical trial of a multipeptide vaccine using TLR agonists and IFA, with correlative studies in 3 immunologic compartments. Methods: This trial is enrolling patients with resected stage IIB-IV melanoma (n=48) and is designed to evaluate the safety and immunogenicity of vaccination with peptides and either of 2 toll-like receptor agonists (TLR3 agonist polyICLC; TLR4 agonist endotoxin), with or without IFA. Patients are vaccinated 6 times over 12 weeks with 12 Class I MHC-restricted nonamer peptides. An immunogenic tetanus helper peptide is included to activate CD4 T cells in the VSME and secondarily to ligate CD40. Goals include safety assessment, measures of CD8 T cell responses, and characterization of cellular and molecular events induced in the blood, VSME and vaccine-draining node (sentinel immunized node, SIN), as well as a preliminary assessment of whether vaccination with TLR agonists improves the persistence of CD8 and CD4 T cell responses to melanoma antigens compared to prior studies with IFA. This includes a first-in-humans evaluation of the safety and immunogenicity of LPS, a classic TLR4 agonist, as a vaccine adjuvant. Thus, there is a novel dose-escalation phase with this adjuvant, which has been safely administered in other settings by intravenous and inhalation routes. An aim of this study is to identify an improved adjuvant for use in future trials combining peptides with other immune therapies. Clinical trial information: NCT01585350.
A phase II study of a yeast-based therapeutic cancer vaccine, GI-6207, targeting CEA in patients with minimally symptomatic, metastatic medullary thyroid cancer.
Authors: Madan Ravi Amrit , Singh Nishith K. , Gramza Ann Wild , Fojo Antonio Tito , Heery Christopher Ryan , Kim Joseph W. , McMahon Sheri , Rauckhorst Myrna , King Thomas H , Apelian David , Schlom Jeffrey , Gulley James L.
Published: March 2020

TPS3127

Background: Saccharomyces cerevisiae has been genetically modified to express CEA protein and developed under a CRADA with GlobeImmune/NCI as a heat-killed immune-stimulating, therapeutic cancer vaccine (GI-6207). A phase I study with GI-6207 demonstrated safety, biomarker stabilization and enhanced immune response in some patients. CEA is over-expressed in multiple malignancies, including medullary thyroid cancer (MTC). Two therapies recently approved by the FDA for metastatic MTC (vandetanib, cabozantinib) come with toxicity and should be reserved for symptomatic/progressive disease. However, a large population of asymptomatic MTC patients has small tumor burden and/or disease that is more indolent. The standard management of these patients is observation. Preliminary data suggest that tumor growth measured by the rate of CEA and calcitonin increase can be quantified in a 3-6 months. Retrospective data from prostate cancer studies suggest vaccines can alter growth rates within 3-4 months. We hypothesize that GI-6207 can alter tumor growth rates in MTC and impact long-term outcome. Methods: A phase II study will evaluate the effect of GI-6207 onthe rates ofincrease in calcitonin in metastatic MTC. 34 patients with minimally symptomatic, radiographically evaluable, metastatic MTC will be randomized 1:1. Arm A will receive vaccine for a year from the time of enrollment. Arm B will receive vaccine after 6 months of surveillance. GI-6207 will be administered subcutaneously at 4 sites (10 yeast units/site), every 2 weeks for 3 months, then monthly up to 1 year. The primary endpoint will compare the effect of GI-6207 on calcitonin kinetics between the vaccine and surveillance arms in the first 6 months. Secondary endpoints include immunologic responses (including antigen-specific T cell responses), objective responses, time to progression, and changes in CEA kinetics. If this trial can prospectively demonstrate that vaccines can alter tumor growth rates, and if such changes are associated with clinical outcomes, then changes in tumor growth rates may become a clinical metric to evaluate vaccine efficacy in MTC and other populations.
Dual anti-HER2 treatment of patients with HER2-positive metastatic colorectal cancer: The HERACLES trial (HER2 Amplification for Colo-rectaL Cancer Enhanced Stratification).
Authors: Marsoni Silvia , Bertotti Andrea , Sartore-Bianchi Andrea , Leone Francesco , Lonardi Sara , Ciardiello Fortunato , Pinto Carmine , Aglietta Massimo , Zagonel Vittorina , Gambacorta Marcello , Grigioni Walter Franco , Rugge Massimo , Risio Mauro , Martino Cosimo , Valtorta Emanuele , Bardelli Alberto , Trusolino Livio , Comoglio Paolo M. , Siena Salvatore
Published: March 2020

TPS3648

Background: We identified HER2 amplification as a potential onco-driver and marker of de novo resistance to anti-EGFR therapy in mCRC PTS for which other known genetic alterations conferring resistance to anti EGFR antibodies were excluded. Exploiting direct transfer xenografts of mCRC surgical samples in mice (xenoPTS), we conducted a multi-arm study in HER2-amplified xenoPTS showing that combinations of lapatinib (L) and trastuzumab (T), or L and pertuzumab (P) induced long-lasting tumor regressions while monotherapy with L led to stabilization and either monotherapy with T or P were ineffective (Bertotti et al. Cancer Discov 2011). The combination of P+T has a strong rationale for treatment of HER2-amplified mCRC, since combining the two agents is synergic in HER2+ breast cancers failing T (Baselga et al. JCO 2010), suggesting a cooperative mechanism of inhibition. On these findings we designed the HERACLES trial. Methods: HERACLES is an independent Phase II, 2-sequential cohort trial, assessing the response rate (RR) of T combined with either L (Cohort A) or P (Cohort B), in m CRC PTS harbouring an amplified HER2 tumor (SISH). Endpoints are RR and PFS. For each cohort sample size was calculated according to the Fleming & Hern 1- stage design under identical assumptions: H0 = RR 10%, H1= RR 30%. With a =0.05, power=0.85, 27 patient are required in each cohort (54 patients overall). A or B will be considered positive if ≥ 6 responses/27 PTS are observed. Detection and quantitation of genetic alterations in circulating tumor DNA (liquid biopsy) and Her2 ECD in plasma as potential markers of secondary resistance will be done q14 days until relapse. Eligibility: CRC histology with KRAS WT, HER2 IHC 3+ ≥50% cells, prior treatment with fluoropirimidines, oxaliplatin, irinotecan, anti EGFR moABs based regimens ± Bevacizumab; measurable disease (RECIST v1.0), ECOG PS ≤1, adequate organ function. Response is assessed q8w. Treatment: L 1000 mg daily po + T 4 mg/kg iv load, then 2 mg/kg iv weekly. Enrollment: since trial start (8/12/12) 198 PTS have been HER2 screened, 10 found positive and 7 are in treatment. EudraCT number : 2012-002128-33. Clinical trial information: 2012-002128-33.
Randomized phase II study of gemcitabine (G), cisplatin (C) with or without veliparib (V) (arms A, B) and a phase II single-arm study of single-agent veliparib (arm C) in patients with BRCA or PALB2-mutated pancreas adenocarcinoma (PC).
Authors: O'Reilly Eileen Mary , Lowery Maeve Aine , Yu Kenneth H. , Capanu Marinela , Stadler Zsofia Kinga , Epstein Andrew S. , Golan Talia , Segal Amiel , Segal Michal , Salo-Mullen Erin E. , Tang Laura H. , Hollywood Ellen , Moynahan Mary Ellen , Do Kinh G , Moore Malcolm J. , Kindler Hedy Lee , Mayer Robert J. , Chen Alice P. , Kelsen David Paul
Published: March 2020

TPS4144

Background: Germline mutations in BRCA1, 2 predispose to PC (Lal, G. Cancer Res, 2000). 5-8% PC have BRCA 1,2 mutations; higher in Ashkenazi Jewish (10-15%). Pre-clinical data demonstrates that platinums and poly-ADP ribose polymerase inhibitors (PARPi) have activity in BRCA-mutated PC models. Early clinical data supporting (Lowery, M. Oncol, 2011). We are evaluating the role of platinum agents and PARPi, veliparib (ABT-888), in BRCA or PALB2-mutated PC. Methods: Arm A, B: Includes non-randomized phase to optimize V dose combined with G, C (Arm A). Subsequently randomized phase II study will evaluate G, C +/- V. Primary endpoint: RECIST 1.1 response rate (RR) G, C, V (Arm A) and G, C (Arm B). Secondary endpoints: Progression-free survival, safety, disease-control rate, overall survival and correlatives involving pre, post biopsies to evaluate mechanisms of sensitivity, resistance to platinums, PARPi. Arm C: Evaluates single-agent V in previously-treated PC. Primary and secondary endpoints similar. Eligibility: BRCA, PALB2-mutated, measurable, stage III/IV PC; Untreated (Arm A, B), ≤ 2 lines therapy (Arm C); ECOG 0-1 (Arm A, B), ECOG 0-2 (Arm C). Treatment Plan: Arm A, B: V PO BID d1-12 (Arm A), q 3 weeks, G 600mg/m2 IV, C 25mg/m2IV, both d3, 10, q 3 weeks (Arm A, B). Arm C: V 400mg PO BID d1-28 q 4 weeks. Biostatistics: Arms A, B: Simon’s 2-stage minimax design per arm. Unacceptable RR 10%, promising 30%, type I, II errors 10%. N= 16 stage I, +N= 9 (stage II). If ≥ 5/25, then promising. If both arms promising, option to add N= 10, allows distinction between RR 20% and 40%, 83% power. Arm C: Simon’s 2-stage, single-arm, uninteresting RR 10%, promising if ≥ 28%. N= 15 stage I, +N= 18 (stage II). Promising RR ≥ 6/33. Total N 47- 95. Contingency for slow accrual. Progress to Date: Accrual: Arm A (non-randomized): 13 screened, N= 5 enrolled. Arm C: 9 screened, N= 4 enrolled. Israeli, Canadian, other U.S. sites opening 2013. Funding and acknowledgements: National Cancer Institute, Lustgarten Foundation. NCT01585805. Clinical trial information: NCT01585805.