bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I/II study of PI3Kinase inhibition with copanlisib combined with the anti-PD-1 antibody nivolumab in relapsed/refractory solid tumors with expansions in MSS colorectal cancer.
Authors: Jakubowski Christopher , Collins Natalie B , Sugar Elizabeth Ann , Berg Maureen , Cao Haihui , Giannakis Marios , Jaffee Elizabeth M. , Azad Nilofer Saba
Published: May 2020

TPS4114

Background: Certain somatic mutations are thought to promote immune evasion and resistance to immunotherapy. PIK3CA was identified in an in vivo genomic screen for mechanisms of resistance to anti-PD1 therapy. MC38 cells (murine colon adenocarcinoma) were engineered to express a library of human cancer-associated mutations from TCGA. Resultant tumors in vivo were exposed to immune pressure with anti-PD1 therapy. Cells that proliferated were then analyzed for mutations that impart immune resistance. Multiple activating mutations in PIK3CA conferred resistance to anti-PD1 therapy. Coadministered PI3K inhibition reversed this resistance. Multiple studies have shown the impact of the phosphatidylinositol 3-kinase (PI3K) pathway on the tumor microenvironment, and 20% of colorectal cancer (CRC) tumors have an activating mutation of PI3K. Methods: A multi-center, open-label, phase I/II study with the combination copanlisib and nivolumab, a PD1 inhibitor, in relapsed/refractory solid tumors with expansions in relapsed/refractory microsatellite-stable (MSS) CRC was developed. Copanlisib is an inhibitor of PI3K and exhibits its most potent inhibitory effect on the isoforms PI3Kα and PI3Kδ. The first phase seeks to determine the maximum tolerated dose (MTD) of copanlisib with fixed dose nivolumab of 480 mg given every 4 weeks. Following determination of the MTD the second phase seeks to determine the 6-month objective response rate of the combination in MSS CRC patients and contains two cohorts 1) PIK3CA wildtype, 2) PIK3CA mutated. The study is planned with 21 evaluable subjects per cohort and allows early termination for lack of efficacy. Tumor assessments will be made using RECIST 1.1. Patients will have a pre-treatment biopsy followed by nivolumab on Day 1 of each 4 week cycle and copanlisib on Day 1, 8 and 15. A second biopsy will occur after six weeks. Eligibility criteria includes completed NGS for PI3K status, and patients must have received at least 2 prior lines of standard therapy. Patients can not have received a prior checkpoint inhibitor or PI3K inhibitor. Secondary and exploratory objectives, in addition to survival and safety outcomes, include exploring immune cell subsets in the local tumor microenvironment and in the peripheral circulation, as well as investigating immune activation and suppressive pathways through RNA expression and additional NGS techniques. The clinical study was activated in January 2019 (NCT03711058). Clinical trial information: NCT03711058 .
A phase Ib/II study of the polo-like kinase 1 (PLK1) inhibitor, onvansertib, in combination with FOLFIRI and bevacizumab for second-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC).
Authors: Ahn Daniel H. , Barzi Afsaneh , Ridinger Maya , Samuelsz Errin , Erlander Mark G. , Bekaii-Saab Tanios S. , Lenz Heinz-Josef
Published: May 2020

TPS4116

Background: Chemotherapy in combination with targeted agents are standard-of-care options for patients for mCRC with response rates >50% in first line. In the second line setting, efficacy of chemotherapy and targeted agents are much lower with response rates of 5% for FOLFIRI (5-fluorouracil, leucovorin, irinotecan) + bevacizumab (anti-VEGF). New treatment options are urgently needed in particular for the 50 % of patients harboring a KRAS mutation. PLK1 is a serine/threonine kinase, master regulator of the mitotic checkpoint and cell division. PLK1 is overexpressed in CRC and its overexpression is associated with poor prognostic. A genome wide RNAi screen identified PLK1 as a synthetic lethal target in KRAS mutant CRC cells, inducing cell cycle arrest and apoptosis upon inhibition. Onvansertib is an oral, highly selective PLK1 inhibitor that demonstrates single agent and synergistic activity with irinotecan in preclinical CRC models. Additionally, KRAS mutated vs wild-type cells showed higher sensitivity to onvansertib. PLK1 inhibition is a potential target in KRAS-mutated mCRC, and the combination of onvansertib + FOLFIRI + bevacizumab may provide a new second-line treatment option. Methods: The primary objective of this single-arm Phase 1b/2 study is to assess the safety and preliminary efficacy of onvansertib in combination with FOLFIRI and bevacizumab in the second line setting for KRAS-mutated mCRC patients. For the Phase 1b segment, a standard 3 + 3 dose-escalation design is used to determine the maximum tolerated dose or recommended phase 2 dose (RP2D) of onvansertib. As of January 24, 2020, enrollment in the second dose level is ongoing. Efficacy will be determined by objective response rate (ORR) according to RECIST v1.1 (primary endpoint), progression-free survival and reduction in KRAS allelic burden in liquid biopsies (secondary endpoints). In the phase 2, based on a one-sided one sample log-rank test with 10% Type I error, there will be at least 90% power to detect an improvement in ORR from 5% to 20% with 26 patients. Exploratory endpoints include genomic studies of circulating tumor cells and ctDNA to evaluate altered pathways that correlate with patient clinical response. Clinical trial information: NCT03829410 .
The PEGASUS trial: Post-surgical liquid biopsy-guided treatment of stage III and high-risk stage II colon cancer patients.
Authors: Lonardi Sara , Montagut Clara , Pietrantonio Filippo , Elez Elena , Sartore-Bianchi Andrea , Tarazona Noelia , Sciallero Stefania , Zampino M. Giulia , Mosconi Stefania , Muñoz Susana , Lazzari Luca , Luraghi Paolo , Siena Salvatore , Sobrero Alberto F. , Labianca Roberto , Torri Valter , Bardelli Alberto , Tabernero Josep , Marsoni Silvia
Published: May 2020

TPS4124

Background: Moving stage III Colon Cancer (CC) into the precision medicine space is a priority in view of the lack of molecular markers driving adjuvant treatment. Retrospective studies have demonstrated the tremendous prognostic impact of circulating tumor DNA (ctDNA) analysis after curative intent surgery, and suggested that lack of conversion of ctDNA from detectable to undetectable after adjuvant chemotherapy reflects treatment failure. With these premises, we have designed the PEGASUS trial (NCT04259944). Methods: PEGASUS is a prospective multicentric study designed to prove the feasibility of using liquid biopsy (LB) to guide the post-surgical and post-adjuvant clinical management in 140 microsatellite stable Stage-III and T4N0 Stage-II CC patients. The LUNAR1 test (Guardant Health, Redwood City, CA, USA) will be used for ctDNA determination. For the efficacy analysis, the PEGASUS cohort will be compared with a 3:1 matched cohort of 420 patients from the TOSCA trial (NCT00646607). A LB executed 2-4 weeks post-surgery will guide a “Molecular Adjuvant” treatment: i) ctDNA+ patients will receive CAPOX for 3 months and ii) ctDNA- patients will receive capecitabine (CAPE) for 6 months but will be retested after 1 cycle, and if found ctDNA+ will be switched to CAPOX treatment. At the end of the “Molecular Adjuvant” treatment a further LB will be performed and instruct subsequent treatment. Positive patients (ctDNA+/+ and ctDNA-/+) will receive an up-scaled “Molecular Metastatic” systemic treatment for 6 months or until radiological progression or toxicity: i) ctDNA+/+ patients will be treated with FOLFIRI; ii) ctDNA-/+ patients with CAPOX. These patients will be subjected to a LB after 3 months and at the end of treatment: in case of positivity will be switched to FOLFIRI. ctDNA+/- patientswill receive a de-escalated treatment with CAPE for 3 months. 3 LB will be performed within 3 months and in case of positivity the patient will be switched to FOLFIRI. Patients with ctDNA-/- will be subjected to an interventional follow-up comprising 2 further LB and in case of positivity they will be switched to CAPOX treatment. PEGASUS is piggybacked to AlfaOmega (NCT04120935), a Master Observational Protocol that will follow patients from diagnosis to 5 years or recurrence/death (whichever comes first), collecting clinical data, radio-images and biological samples. AlfaOmega provides a clinical and logistic ecosystem for the seamless integration of PEGASUS clinical results with the biological underpinning of colon cancer. Clinical trial information: NCT04259944 .
Phase I study of proton therapy in adjuvant pancreatic cancer (PROTON-PANC).
Authors: Weinberg Benjamin Adam , Wang Hongkun , He Aiwu Ruth , Villa Nicole , Unger Keith Robert
Published: May 2020

TPS4663

Background: Pancreatic adenocarcinoma (PAC) has a poor prognosis, with a 5-year survival rate of 10%. The current standard of care for patients with resectable disease is surgical resection followed by 6 months of adjuvant modified FOLFIRINOX (FFX, leucovorin, fluorouracil, irinotecan, and oxaliplatin). As survival outcomes and distant recurrence improve with the use of FFX, locoregional recurrence remains a cause of morbidity and mortality. We seek to integrate adjuvant short-course proton radiation therapy (PRT) to the surgical bed in between cycles of FFX. While there is limited literature on the combination of short course PRT and FFX, there are analogous experiences using 5 fraction SBRT or IMRT following FFX in routine clinical practice. The ongoing Alliance 021501 trial of preoperative chemotherapy vs. chemotherapy plus radiation (IMRT using 5 Gy X 5 or SBRT 6.6 X 5) in borderline resectable pancreatic cancer mandates that radiation starts 5 days or more following the last dose of FFX. Additionally, at the Lombardi Comprehensive Cancer Center, we routinely combine 5 fraction SBRT after a 10-14 day interval from FFX. Methods: This is a phase I, single-arm, open-label study. Eligible pts are ≥ 18 years old, have histologically confirmed, resected PAC of the pancreatic head (R0 or R1) on adjuvant FFX, an ECOG performance status of 0-1, and adequate normal bone marrow and hepato-renal function. Exclusion criteria are prior radiation to the upper abdomen (neoadjuvant chemotherapy is allowed). This study will use a 3+3 dose-escalation design to determine the safety and feasibility of combining 5 fractions of adjuvant PRT with FFX using different intervals between cycle 6 of FFX and PRT: dose level 1 uses a 12 day interval, and dose level 2 uses a 5 day interval. The primary endpoint is to determine the RP2D between the 2 proposed schedules. Using a 3+3 dose-escalation schema, 2-12 patients will be required to determine the RP2D. Enrollment began in Q4 2019. Clinical trial information: NCT03885284 .
Adaptive dose optimization trial of stereotactic body radiation therapy (SBRT) with or without GC4419 (avasopasem manganese) in pancreatic cancer.
Authors: Moser Elizabeth Charlotte , Hoffe Sarah E. , Frakes Jessica , Aguilera Todd Anthony , Karim Mona , Colbert Lauren Elizabeth , Moningi Shalini , Tzeng Ching-Wei David , Thall Peter F. , Pant Shubham , Bhutani Manoop S. , Brookes Melissa , Holmlund Jon , Herman Joseph M. , Taniguchi Cullen M.
Published: May 2020

TPS4670

Background: Local progression causes up to 30% of deaths from pancreatic cancer (PC) and is also a significant source of morbidity. Stereotactic body radiotherapy (SBRT) offers the potential for improved therapeutic index over standard fractionation, but current regimens of 5 fractions of 5-7 Gy/fraction are constrained by nearby organ tolerance and offer only palliation without improving survival. Safe dose escalation may be necessary to improve SBRT efficacy. Avasopasem, a superoxide dismutase mimetic, selectively converts superoxide (O2•-) to hydrogen peroxide (H2O2) and oxygen. O2•-initiates normal tissue damage due to RT. Avasopasem is in a Phase 3 trial (NCT03689712) to reduce RT-induced oral mucositis in head and neck cancer, based on positive results in a randomized Phase 2 trial for that indication (Anderson, JCO 2019). Avasopasem improved the survival of mice receiving 8.5 Gy x 5 to the upper abdomen. Cancer cells are less tolerant to elevated H2O2, and more tolerant to elevated O2•-, than normal cells, and avasopasem demonstrated mechanism-dependent synergy with high dose-fraction RT in a human tumor xenograft with inducible expression of catalase (Sishc, AACR 2018). Thus, adding avasopasem to SBRT may increase both the efficacy and the safety of the latter. Methods: 48 patients with locally advanced PC, who have completed medically-indicated induction chemotherapy, are randomized 1:1 to placebo or avasopasem, 90 mg IV, prior to each of 5 consecutive daily (M-F) SBRT fractions. A phase I/II Late Onset Efficacy/ Toxicity tradeoff (LO-ET) based adaptive design adaptive model drives assignment of SBRT dose escalation in each arm based on a dual endpoint (Gr 3-4 GI toxicity or death; local stable disease or better) by 90 days post SBRT. The planned dose levels are 10, 11 and 12Gy x 5 fractions (BED10 = 100,112.5 and 132Gy, respectively) as an integrated boost to the gross tumor volume (GTV). Primary endpoint: Maximum tolerated dose of SBRT with avasopasem or placebo. Secondary endpoints progression-free survival, response rate, and acute (90 day) and late (12 month) radiation toxicity with avasopasem vs placebo. Exploratory correlative studies include ctDNA, tumor exome/transcriptome sequencing, and immune profiling. Clinical trial information: NCT03340974 .
Hcrn GU15-215: A phase II trial of atezolizumab (atezo) and bevacizumab (bev) in cisplatin-ineligible patients (pts) with advanced/unresectable urothelial cancer (UC).
Authors: Balar Arjun Vasant , Funt Samuel Aaron , Gupta Shilpa , Dudek Arkadiusz Z. , Boiles Alejandro Recio , Vaena Daniel A. , Kilari Deepak , Rosenberg Jonathan E.
Published: May 2020

TPS5098

Background: Atezolizumab is a standard of care in selected cisplatin-ineligible pts with advanced UC. VEGF targeted therapies have activity in advanced UC and may lead to immune synergy when combined with anti-PD-1/L1 therapy. This phase II study is investigating the combination of bevacizumab and atezolizumab in untreated cisplatin-ineligible pts with advanced UC. Methods: HCRN GU15-215 (NCT03272217) is a phase 2, multicenter single arm trial to evaluate the efficacy and safety of atezolizumab and bevacizumab in pts with advanced UC. Cisplatin-ineligible pts (defined as any of estimated CrCl < 60 cc/min, Grade ≥ 2 hearing loss or neuropathy, ECOG PS 2 or solitary kidney) with untreated, histologically confirmed locally advanced or metastatic UC irrespective of PD-L1 expression status and with sufficient pre-treatment tumor tissue available for biomarker analysis are eligible. Pts who have received perioperative chemotherapy are eligible, however prior treatment with a checkpoint inhibitor is excluded. Pts with NYHA Class II or greater heart failure, significant cerebrovascular or cardiac disease within 3 months, uncontrolled HTN, persistent gross hematuria, and GI obstruction or perforation within 6 months are excluded. 70 pts will receive treatment with atezolizumab 1200 mg IV plus bevacizumab 15 mg/kg IV every 21 days. All pts will undergo an on-treatment biopsy before cycle 2 if safe and feasible. Peripheral blood samples and stool samples will be collected before treatment and on-treatment for immune-relevant biomarker analyses. Cross-sectional imaging will be performed every 9 weeks on therapy for the first 12 months and then every 12 weeks thereafter to assess for response. Subjects will be eligible to continue treatment until RECIST v1.1 defined progression or unacceptable toxicity for up to 24 months. The primary endpoint is overall survival rate at 1 year and will be analyzed by the Kaplan Meier method. Key secondary endpoints include objective response rate, duration of response, disease control rate, progression-free survival and safety and toxicity as defined by CTCAE version 4.0. Clinical trial information: NCT03272217 .
A randomized phase II study of nivolumab plus ipilimumab versus standard of care in previously untreated and advanced non-clear cell renal cell carcinoma (SUNIFORECAST).
Authors: Ahrens Marit , Escudier Bernard , Boleti Ekaterini , Grimm Marc-Oliver , Gross-Goupil Marine , Barthelemy Philippe , Gravis Gwenaelle , Bedke Jens , Ivanyi Philipp , Panic Andrej , Zschaebitz Stefanie , Negrier Sylvie , Mellado Begona , Biel Anika , Waddell Tom , Maroto Pablo , Retz Margitta , Boegemann Martin , Hartmann Arndt , Bergmann Lothar
Published: May 2020

TPS5103

Background: Non-clear cell renal cell carcinomas (nccRCC) are a heterogeneous group of tumors accounting for approximately 25% of RCC patients (pts.). Since most clinical trials focus on clear-cell RCC (ccRCC) only, data on treatment strategies for nccRCC are limited. The combination of Nivolumab and Ipilimumab (IO/IO) has recently been approved for treatment in RCC showing a significant improvement in overall response rate (ORR), progression free (PFS), and overall survival (OS) in intermediate and high-risk pts. compared to sunitinib in a phase-III trial. Furthermore retrospective analysis in nccRCC patients have shown promising results for IO/IO as well in these entities. Methods: In this prospective randomized phase-II multicenter European trial adults with advanced or metastatic nccRCC without prior systemic therapy are eligible. Other key inclusion criteria include: available tumor tissue, Karnofsky > 70% and measurable disease per RECIST 1.1. All histological diagnoses are reviewed by a central pathologist. The study plans to randomize ~306 pts. stratified for papillary or non-papillary non-clear cell histology and by the International Metastatic RCC Database Consortium (IMDC) risk score. Pts. will be randomized 1:1 to either i) Nivolumab 3mg/kg intravenously (IV) plus Ipilimumab 1mg/kg IV every 3 weeks for 4 doses followed by Nivolumab fixed dose 240mg IV every 2 weeks or ii) standard of care therapy according to the approved schedule. Treatment will be discontinued in case of unacceptable toxicity or withdrawal of informed consent. Pts may continue treatment beyond progression, if clinical benefit is achieved and treatment is well tolerated. Primary endpoint is the OS rate at 12 months. Secondary endpoints include OS rate at 6 and 18 months, median OS, PFS, ORR and quality of life. The trial is in progress and 122 patients (78 pts with papillary, 37 pts with non-papillary histology) have been enrolled until now. Clinical trial information: NCT03075423 .
Phase I study of AMG 160, a half-life extended bispecific T-cell engager (HLE BiTE immune therapy) targeting prostate-specific membrane antigen, in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Tran Ben , Horvath Lisa , Rettig Matthew , Fizazi Karim , Lolkema Martijn P. , Dorff Tanya B. , Greil Richard , Machiels Jean-Pascal H. , Autio Karen A. , Rottey Sylvie , Adra Nabil , Garje Rohan , Roncolato Felicia , Tagawa Scott T. , Shariat Shahrokh F. , Salvati Mark , Poon Shirley , Kouros-Mehr Hosein
Published: May 2020

TPS5590

Background: Prostate-specific membrane antigen (PSMA) is a clinically validated therapeutic target for the imaging and treatment of mCRPC. AMG 160 is an HLE BiTE immune therapy designed to redirect T cells to cancer cells by binding to PSMA on cancer cells and CD3 on T cells. BiTE immune therapy leads to direct tumor cell killing, T-cell activation and expansion, and the creation of a pro-inflammatory tumor microenvironment. Combining AMG 160 with a PD-1 inhibitor may enhance antitumor activity by enabling sustained T-cell-dependent killing of tumor cells in the inflamed tumor microenvironment. Methods: NCT03792841 is a phase I study of AMG 160 as monotherapy (part 1) and in combination with pembrolizumab (part 2) in men with histologically/cytologically confirmed mCRPC who are refractory to a novel hormonal therapy (abiraterone, enzalutamide, and/or apalutamide) and have failed 1–2 taxane regimens (or are medically unsuitable or have refused taxanes), who have ongoing castration with total serum testosterone ≤ 50 ng/dL, and have evidence of progressive disease. Patients who received prior PSMA radionuclide therapy may be eligible. Patients with CNS metastases, leptomeningeal disease, spinal cord compression, or active autoimmune disease will be excluded. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of AMG 160 given as monotherapy or in combination with pembrolizumab. Secondary objectives are to characterize pharmacokinetics and preliminary antitumor activity. Exploratory objectives include evaluation of potential pharmacodynamic and patient selection biomarkers, immunogenicity, and patient-reported pain and functional outcomes. The part 1 dose exploration will determine the MTD/RP2D of AMG 160. The part 1 dose expansion will confirm the safety and tolerability of the MTD/RP2D. The part 2 dose exploration will estimate the MTD/RP2D of AMG 160 in combination with pembrolizumab. Evaluation of preliminary antitumor activity will be based on RECIST 1.1 with Prostate Cancer Working Group 3 modifications, PSA response, CTC response, progression-free survival (radiographic and PSA), and overall survival. PSMA PET/CT and FDG PET/CT imaging will be used for evaluation of exploratory objectives. The study opened in February 2019 and is currently recruiting patients into both part 1 and part 2. Clinical trial information: NCT03792841 .
Phase III study of pembrolizumab (pembro) plus enzalutamide (enza) and androgen deprivation therapy (ADT) for patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): KEYNOTE-991.
Authors: Gratzke Christian , Burgents Joseph E , Niu Cuizhen , Poehlein Christian Heinrich , Drake Charles G.
Published: May 2020

TPS5595

Background: Pembro, an anti–PD-1 antibody, has shown antitumor activity as monotherapy and in combination with other agents in metastatic castration-resistant prostate cancer (mCRPC). As the antitumor effects of enza may be pro-immunogenic, we hypothesized that combining pembro and enza could show additive or synergistic antitumor activity. Furthermore, pembro + enza previously showed antitumor activity in pts with mCRPC for whom abiraterone failed (KEYNOTE-365, NCT02861573) and in pts with mCRPC for whom enza monotherapy failed (KEYNOTE 199, NCT02787005). These data warrant further evaluation of the combination of pembro + enza when given at the initiation of ADT. Methods: KEYNOTE-991 (NCT04191096) is a phase III trial to evaluate the efficacy and safety of enza + ADT + either pembro or placebo in patients with mHSPC. Approximately 1232 pts will be randomly assigned 1:1 to receive enza 160 mg orally once daily + ADT + pembro 200 mg IV every 3 weeks (Q3W) or enza 160 mg orally once daily + ADT + placebo IV Q3W. ADT is receipt of an LHRH agonist or antagonist during study treatment or bilateral orchiectomy. Treatment will be stratified by prior docetaxel therapy (yes or no) and presence of high-volume disease (yes or no). Pts with mHSPC, with ≥2 bone lesions and/or visceral disease, who are naive to next-generation hormone agents, and who have ECOG PS 0 or 1 are eligible. Pts must provide tissue for biomarker analysis. Responses will be assessed by CT or MRI and radionuclide bone imaging per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q12W from the date of randomization. Treatment will continue with pembro for up to 35 cycles, and treatment with enza will proceed continuously from day 1 of cycle 1 until disease progression, unacceptable toxicity, or withdrawal of consent. Dual primary end points are radiographic progression-free survival (PFS) per PCWG3-modified RECIST v1.1 assessed by BICR and overall survival. Secondary end points are time to first subsequent anticancer therapy, time to symptomatic skeletal-related event, PFS2 (progression after next line of therapy or death), prostate-specific antigen (PSA) response rate, time to PSA progression, PSA undetectable rate, objective response rate, duration of response, and time to radiographic soft tissue progression. Other end points are safety and patient-reported outcomes (eg, time to pain progression). Clinical trial information: NCT04191096 .
ADAPTcycle: Adjuvant dynamic marker-adjusted personalized therapy (ADAPT) comparing endocrine therapy plus ribociclib versus chemotherapy in intermediate-risk HR+/HER2- early breast cancer (EBC).
Authors: Harbeck Nadia , Gluz Oleg , Christgen Matthias , Graeser Monika , Hilpert Felix , Krauss Katja , Thill Marc , Warm Mathias , Müller Volkmar , Braun Michael Wilhelm , Just Marianne , Kreipe Hans Heinrich , Nitz Ulrike , Kates Ronald E. , Schinkoethe Timo , Wuerstlein Rachel , Kuemmel Sherko
Published: May 2020

TPS601

Background: The WSG ADAPT trial program represents the concept of individualization of (neo)-adjuvant decision-making in EBC in a subtype-specific manner. The first WSG ADAPT umbrella trial aimed to establish early predictive molecular surrogate markers for response after a short 3-week induction treatment. The goals of the WSG ADAPT trial program are early response assessment and subtype-specific therapy tailoring to those patients who are most likely to benefit. Methods: WSG-ADAPTcycle is a prospective, multi-center, interventional, two-arm, open-label, (neo)adjuvant, non-blinded, randomized, controlled phase III trial (NCT04055493). It investigates whether patients (pts.) with HR+/HER2- EBC identified during screening as intermediate risk (based on Oncotype DX and response to 3 weeks of preoperative endocrine therapy [ET]) derive additional benefit from 2 years of the CDK4/6 inhibitor ribociclib combined with ET compared to chemotherapy (CT) (followed by standard ET). Co-primary endpoints are disease-free survival (DFS) and distant DFS. It is planned to screen 5600 pts and to randomize 1670 pts in a 3:2 ratio (ribociclib + ET/CT). Study start was in July 2019 (80 sites, enrollment period 36 months) and until date of submission, 180 pts. have been screened and 40 randomized. Pts with HR+/HER2- EBC with clinically enhanced risk (cT2-4 or Ki67 20% or G3 or cN+) are eligible if they fulfill the ADAPT intermediate-risk group criteria: either Recurrence Score (RS) ≤25 and Ki67postendocrine>10%, RS >25 and Ki67postendocrine<10% in p/cN0-1 pts, or RS ≤25 and Ki67postendocrine<10% in c/pN2-3 pts. Treatment duration is 2 years for the ribociclib + ET (premenopausal: AI + GnRH) arm and 16-24 weeks for the CT arm; treatment is possible either in the neoadjuvant (ET + ribociclib duration 16 – 32 weeks) or adjuvant setting. ePROs are collected using CANKADO; ECG monitoring is performed using a novel cardiology-supported CANKADO-based eHealth method. Translational analyses: Exploratory tissue biomarker research will be conducted to assess alterations in molecular markers. In addition, ctDNA/ctRNA from optional blood samples will be assessed for mutations and gene expression. Conclusions: ADAPTcycle seeks to evaluate whether endocrine-based therapy with ET and a CDK 4/6 inhibitor is superior to CT followed by ET in patients with luminal EBC who may be undertreated with ET alone (based on either lack of endocrine responsiveness or high tumor burden). Clinical trial information: 2018-003749-40 .
A phase III trial of nivolumab with neoadjuvant chemotherapy and adjuvant endocrine therapy in ER+/HER2- primary breast cancer: CheckMate 7FL.
Authors: Loi Sherene , McArthur Heather L. , Harbeck Nadia , Pusztai Lajos , Delaloge Suzette , Letrent Kristen , Chen Tian , Li Bin , Tatsuoka Kay , Zardavas Dimitrios , Curigliano Giuseppe
Published: May 2020

TPS604

Background: Patients (pts) diagnosed with primary estrogen receptor-positive (ER+), human epidermal growth factor 2-negative (HER2−) breast cancer (BC) of high grade and/or low ER expression are at increased risk of relapse, despite current standard of care (SoC). Promising data assessing programmed death-1 (PD-1) inhibition coupled with neoadjuvant chemotherapy for pts with high-risk ER+, HER2− BC noted improved pathologic complete response (pCR), which is identified as a valid surrogate endpoint for long-term clinical outcomes. Methods: CheckMate 7FL (NCT04109066) is a randomized, double-blind, placebo-controlled, multicenter, global phase 3 study evaluating nivolumab (NIVO) vs placebo (PBO) in combination with neoadjuvant chemotherapy and adjuvant endocrine therapy (ET) in pts with high-risk, ER+, HER2− primary BC. Eligible pts are male or female, aged ≥18 years with newly diagnosed grade 2 with ER expression of 1–9%, or grade 3, T1c-2, cN1-2 (tumor size ≥2 cm) or T3-T4, cN0-cN2 ER+, HER2− BC. Pts eligible for neoadjuvant chemotherapy and surgery, with adequate organ function, ECOG PS of 0 or 1, and tissue available for biomarker assessments will be enrolled. Approximately 1200 pts will be randomized 1:1 to NIVO or PBO, stratified by programmed death ligand 1 (PD-L1) expression, tumor grade (2 or 3), axillary nodal status (+ or −), and anthracycline + cyclophosphamide schedule (Q3W or Q2W). In the neoadjuvant phase, pts will receive NIVO 360 mg Q3W or PBO + paclitaxel 80 mg/m2 QW for four 3-week cycles, followed by NIVO 360 mg Q3W (or 240 mg Q2W) or matching PBO in combination with either doxorubicin 60 mg/m2 or epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 Q3W or Q2W for 4 cycles. Pts will undergo surgery after completion of the neoadjuvant phase. Following surgery, pts will enter the adjuvant phase and receive NIVO 480 mg Q4W or PBO for 7 cycles + investigator’s choice of ET per local SoC. Primary endpoints are pCR (ypT0/is, ypN0) and event-free survival. Secondary endpoints include overall survival, disease-free survival, distant-metastasis-free survival, safety, pCR (ypT0 ypN0 and ypT0/is) rates, overall response rates, residual cancer burden, and quality of life. Interim analyses are planned. The study is currently enrolling. Clinical trial information: NCT04109066 .
Phase Ib/II trial of tisotumab vedotin (TV) ± bevacizumab (BEV), pembrolizumab (PEM), or carboplatin (CBP) in recurrent or metastatic cervical cancer (innovaTV 205/ENGOT-cx8/GOG-3024).
Authors: Vergote Ignace , Concin Nicole , Mirza Mansoor Raza , Andreassen Camilla Mondrup , Lorusso Domenica , Gennigens Christine N. , Banerjee Susana N. , O'Cearbhaill Roisin Eilish , Campos Susana , Viana Nicacio Leonardo , Eaton Lamar , O'Malley David M. , Soumaoro Ibrahima , Monk Bradley J.
Published: May 2020

TPS6095

Background: Patients (pts) with recurrent/metastatic cervical cancer (r/mCC) receive paclitaxel/platinum or paclitaxel/topotecan ± BEV as first-line standard-of-care therapy. Tissue factor (TF) expression has been associated with poor prognosis in solid tumors, and TF is highly expressed in r/mCC. TV is an investigational antibody-drug conjugate composed of a fully human, TF-directed monoclonal antibody covalently attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. Upon internalization, MMAE is released resulting in cell cycle arrest and apoptotic cell death. In pts with previously treated r/mCC, TV monotherapy (IV 2.0 mg/kg Q3W) demonstrated a manageable safety profile and encouraging antitumor activity (investigator-assessed confirmed ORR, 24%; median DOR, 4.2 mo) [Hong DS et al. Clin Cancer Res. 2019. doi: 10.1158/1078-0432.CCR-19-2962]. The preliminary safety and efficacy data for TV monotherapy suggest a positive benefit/risk profile and warrant further investigation of TV in combination with therapies commonly administered to pts with r/mCC. The global, open-label, phase Ib/II trial innovaTV 205/ENGOT-cx8/GOG-3024 (NCT03786081) evaluates the safety and antitumor activity of TV monotherapy and TV in combination with BEV, PEM, or CBP in pts with untreated or previously treated r/mCC. This abstract presents the new TV monotherapy weekly dosing schedule. Results from this study will inform the further clinical development of TV in the treatment of r/mCC. Methods: Approximately 170 adult pts with recurrent or stage IVB squamous, adenosquamous, or adenocarcinoma of the cervix; measurable disease; and ECOG PS 0-1 will be enrolled. The phase I part of the study will consist of 3 dose-escalation arms for identification of the recommended phase II dose (RP2D) of TV administered Q3W with BEV, PEM, or CBP. In this part, previously treated pts will receive escalating doses of TV (IV Q3W) in combination with escalating doses of BEV (IV Q3W), a fixed dose of PEM (IV Q3W), or a fixed dose of CBP (IV Q3W). The phase II part will include 4 expansion arms. In this phase, pts who have not received prior systemic therapy for r/mCC will receive 1) TV RP2D + PEM or 2) TV RP2D + CBP; pts who received 1-2 prior treatments for r/mCC will receive 3) TV RP2D + PEM or 4) TV monotherapy with weekly dosing (IV 3Q4W). The primary endpoint of phase II is ORR by RECIST v1.1. Secondary endpoints include DOR, time to response, PFS, OS, and safety. Clinical trial information: NCT03786081.
SIENDO/ENGOT-EN5: A randomized phase III trial of maintenance with selinexor/placebo after combination chemotherapy in patients with advanced or recurrent endometrial cancer.
Authors: Vergote Ignace , Hamilton Erika Paige , Romero Ignacio , Guerra Eva M. , Buscema Joseph , Laenen Annouschka , Perri Tamar , Estévez-García Purificación , Gomez Raposo Cesar , Levy Tally , Valabrega Giorgio , Martinez Garcia Jeronimo , Mangili Giorgia , Makker Vicky , Michel Dayana , Wang Hongwei , Mirza Mansoor Raza
Published: May 2020

TPS6105

Background: Endometrial cancer is one of the most common gynecologic malignancies with increasing incidence and mortality. Patients with advanced disease that has relapsed or received prior platinum-based therapy or radiotherapy have limited options and the prognosis remains poor. Selinexor is a novel, oral selective inhibitor of nuclear export (SINE) which forces nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone was recently approved for patients with multiple myeloma. In addition, single agent selinexor has demonstrated broad activity in other hematologic malignancies and solid tumors. In a phase II study, 50 mg/m2 (~80 mg) selinexor administered twice weekly demonstrated a disease control rate of 35% with 2 confirmed partial responses among 23 patients with heavily pretreated endometrial cancer (Vergote I et al. Gynecol Oncol 2020). In the absence of approved maintenance therapies, we conducted this study to evaluate the efficacy of selinexor compared with placebo as maintenance therapy in patients with advanced or recurrent endometrial cancer. Methods: This is a multicenter, double-blind, placebo-controlled, randomized phase III study in patients in partial or complete remission after completing at least 12 weeks of taxane-platinum combination therapy for primary Stage IV disease and recurrent disease (i.e., relapse after primary therapy for early stage disease including surgery and/or adjuvant therapy). A total of 192 patients will be enrolled at 80 sites in Europe, North America, and Israel. Patients will be randomized in a 2:1 ratio to either maintenance therapy with 80 mg oral selinexor once weekly or placebo. Stratification factors include primary Stage IV versus first recurrent disease at the time of taxane-platinum therapy and disease status after chemotherapy (partial versus complete response). Treatment will continue until disease progression. The primary endpoint is progression free survival (PFS) per RECIST v1.1. Secondary endpoints include disease-specific survival, overall survival, time to first subsequent therapy, time to second subsequent therapy, PFS on subsequent therapy and safety and tolerability. The study is currently open and enrolling patients. Clinical trial information: NCT03555422.
Head-to-head comparison of the non-G-CSF small molecule single agent (SA) plinabulin with SA pegfilgrastim for the prevention of docetaxel chemotherapy (chemo)-induced neutropenia (CIN) in the protective-1 trial.
Authors: Blayney Douglas W. , Huang Lan , Mohanlal Ramon W.
Published: May 2020

TPS7087

Background: Plinabulin (Plin) is a small molecule with anti-cancer activity and CIN effects. The Phase (Ph) 2 clinical trial NPI-2358-101 ( NCT00630110 ) evaluated Plin at 20 or 30 mg/m2 on Day (D) 1 and D8) plus D1 Docetaxel (Doc) 75 mg/m2 combination versus D1 Doc alone in patients (pts) with non-small cell lung cancer(NSCLC). In a large ( > 70%) subset of pts with a measurable lung lesion in the lung (per RECIST 1.1) receiving 30 mg/m2 Plin + Doc (n = 38), mOS was 4.6 months longer vs Doc alone (n = 38) (Mohanlal ASCO-SITC 2018). An unexpected post-hoc finding was a CIN benefit with adding at 20 or 30 mg/m2 Plin to Doc: 33% of pts in the Doc arm had grade 4 neutropenia, whereas in the Plin +Doc group 4% of pts (P < 0.0003) (Blayney ASH 2018). Plin boost the number the number of hematopoietic/progenitor cells in bone marrow. We subsequently initiated two global Ph3 programs with Plin: 1. A Ph 3 trial confirming its anticancer activity in NSCLC (study BPI-2358-103; NCT02504489; this trial is ongoing) and 2. An evaluation of Plin for CIN prevention through studies BPI-2358-105 (NCT03102606; PROTECTIVE-1), and study 106 (NCT03294577; PROTECTIVE-2). We previously reported from the Ph 2 portion of study 105, that SA Plin and Pegfigrastim (Peg) had comparable protection against CIN induced by Doc, however in contrast to Peg, Plin did not cause bone pain or thrombocytopenia (Blayney IASLC 2018, ESMO 2018). Plin is given by 30 min IV infusion on the same day of Chemo, 30 min after Chemo. The Ph3 portion of Study 105 in ongoing. Methods: In the Ph 3 portion of PROTECTIVE-1, pts with NSCLC, HRPC or BC are randomized (1:1) to either Plin 40 mg (over 30 minutes on D1; n = 75) or Peg 6mg (on D2, n = 75), and the primary endpoint is Duration of Severe Neutropenia (DSN). Plin 20 mg/m2 is similar to a 40 mg fixed dose. Absolute neutrophil counts (ANC) is determined on D 0, 1,2,3,6,8,9,10, 15 in Cycle 1 The trial aims to demonstrate non-inferiority of Plin vs Peg. Non-inferiority will be declared if the non-inferiority margin (NIM) of 0.65 day will be met, which NIM is more conservative than the 1 day NIM, typically employed for G-CSG biosimilar trials. Pts should have at least 1 risk factor as per NCCN guidelines.The trial is double-blinded to enable reliable PRO, Bone Pain and QoL assessments through validated questionnaires (EQ-5D-5L; EORTC QLQ-C30; Wang Baker Faces Pain Rating Scale). Following an Interim Analysis, the trial will continue without modifications. Clinical trial information: NCT03102606 .
A phase II study of BP1001 (liposomal Grb2 antisense oligonucleotide) in patients with hematologic malignancies.
Authors: Ohanian Maro , Lin Tara L. , Craig Michael , Agrawal Apurv , Halka Kathleen , Tari Ashizawa Ana , Cortes Jorge E. , Roboz Gail J.
Published: May 2020

TPS7561

Background: The growth factor receptor bound protein-2 (Grb2) is vital to oncogene signaling and tumor progression. BP1001 is a liposome-incorporated Grb2 antisense oligonucleotide that inhibits Grb2 expression. Grb2 inhibition suppresses cancer growth and survival. A Phase I/Ib single center study in patients with refractory/relapsed leukemias demonstrated the safety of BP1001 up to 90 mg/m2 dose and the efficacy of BP1001 in combination with low dose cytarabine (LDAC) in refractory/relapsed acute myeloid leukemia (AML) patients (Ohanian, Lancet Haematol 2018). Based on pharmacokinetic (PK) considerations, the recommended Phase II dose was 60 mg/m2. A phase II study was initiated to explore the clinical impact of BP1001 in combination with LDAC in untreated AML patients. Interim safety and efficacy of BP1001 + LDAC in untreated AML patients was presented at the 2018 Annual ASH Meeting. BP1001 was safely administered to 25 patients with untreated AML, who were considered unfit for standard chemotherapy. Efficacy data compared favorably to what has been reported with available options for unfit patients largely with secondary AML or adverse-risk AML. Since the Interim Data presentation, the study was amended to investigate BP1001 + decitabine combination and include myelodysplastic syndrome (MDS) patients. This is because BP1001 enhanced decitabine anti-leukemic effects in preclinical studies. Methods: This is a multi-center, open-label study with 2 parallel cohorts of BP1001 + decitabine treatment in untreated AML/high risk MDS patients and refractory/relapsed AML/high risk MDS patients who are considered by the investigator unsuitable for or refused intensive chemotherapy. BP1001 is given intravenously (IV) at 60 mg/m2 twice weekly. Decitabine is given 20 mg/m2 IV daily for 5 consecutive days. Each cycle is 28 days. Each cohort can enroll 19 patients, with a decision to stop or proceed to 54 patients. The primary objective of this study is to assess whether BP1001 + decitabine provides higher complete remission rates than decitabine alone (by historical comparison) in AML/high risk MDS patients. The secondary objectives of this study are to assess: Safety of BP1001 + decitabine; partial remissions and blast count reductions; overall survival, time to response and duration of response; minimal residual disease status in patients who achieve complete remission; and plasma PK profile of BP1001. The exploratory objective of this study is to evaluate the association of treatment response with cytogenetic and molecular characteristics. Clinical trial information: NCT02781883 .
Trial in progress: A phase III, randomized, open-label study comparing zanubrutinib plus rituximab versus bendamustine plus rituximab in patients with previously untreated mantle cell lymphoma (MCL).
Authors: Dreyling Martin H. , Tam Constantine Si Lun , Wang Michael , Smith Stephen Douglas , Ladetto Marco , Huang Huiqiang , Elstrom Rebecca L. , Co Melannie , Holmgren Eric , Huang Jane , Le Gouill Steven
Published: May 2020

TPS8071

Background: Bruton tyrosine kinase (BTK) mediates B-cell proliferation, migration, and adhesion. BTK inhibition has emerged as a strategy for targeting B-cell malignancies, including MCL. Zanubrutinib is a next-generation BTK inhibitor that was designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases, with favorable pharmacokinetic and pharmacodynamic properties. Zanubrutinib monotherapy has been evaluated in 118 patients (pts) with relapsed/refractory MCL in 2 single-arm studies: BGB-3111-206 [NCT03206970] and BGB-3111-AU-003 [NCT02343120]. The overall response rate (ORR) by independent review committee (IRC) in both trials was 84% with median durations of response of 19.5 and 18.5 months, respectively. First-line treatment for MCL has failed to cure most pts, particularly elderly or transplant-ineligible groups, and chemotherapy-based approaches result in cumulative, long-term risks. The study described herein is designed to evaluate the safety and efficacy of zanubrutinib plus rituximab versus bendamustine plus rituximab in elderly pts and pts with comorbidities with previously untreated MCL who are ineligible for stem cell transplant. Methods: This ongoing phase 3, open-label study will enroll ≈500 pts to be randomized 1:1, stratified by MCL International Prognostic Index score (low vs intermediate/high), age ( < 70 vs ≥70 years), and geographic region (North America/Europe vs Asia-Pacific). In arm A, pts will receive up to six 28-day cycles of oral zanubrutinib 160 mg twice daily in combination with intravenous (IV) rituximab 375 mg/m2 on day 1 of each cycle. After 6 cycles, zanubrutinib will continue as a monotherapy until progressive disease, unacceptable toxicity, or withdrawal of consent. In arm B, pts will receive up to six 28-day cycles of IV bendamustine 90 mg/m2 on days 1 and 2 of each cycle and rituximab 375 mg/m2 on day 1 of each cycle, followed by observation. Eligible pts must have histologically confirmed MCL and be aged ≥70 years, or 65-69 years with defined comorbidities. Disease response will be assessed per the 2014 Lugano Classification for non-Hodgkin lymphoma. The primary endpoint is progression-free survival (PFS) determined by IRC. Key secondary end points include PFS by investigator assessment, ORR, time to and duration of response, overall survival, and safety. Recruitment is ongoing. Clinical trial information: NCT04002297 .
Subcutaneous daratumumab in patients with multiple myeloma who have been previously treated with intravenous daratumumab: A multicenter, randomized, phase II study (LYNX).
Authors: Bahlis Nizar J. , Zonder Jeffrey A. , Wroblewski Susan , Qi Ming , Renaud Thomas , Jackson Carolyn Chang , Facon Thierry
Published: May 2020

TPS8553

Background: The intravenous (IV) formulation of daratumumab (DARA), a human CD38-targeted monoclonal antibody, is approved in many countries for use as monotherapy in relapsed/refractory multiple myeloma (RRMM) and in combination with standard-of-care regimens in RRMM or newly diagnosed MM. A subcutaneous (SC) formulation of DARA is under investigation in several ongoing studies. In the phase 3 COLUMBA study, DARA SC was shown to be non-inferior to DARA IV, demonstrating similar efficacy and pharmacokinetics, with a significantly decreased rate of infusion-related reactions and reduced administration time. The phase 2 LYNX (MMY2065) study will evaluate the efficacy and safety of retreatment with DARA. Methods: In this ongoing, multicenter, open-label, randomized phase 2 study, ~230 patients (pts) with prior exposure to DARA will be randomized 1:1 to receive carfilzomib and dexamethasone (Kd) ± DARA. Pts must have received 1 to 2 prior lines of therapy (at least one of which included DARA IV), with DARA-based therapy completed ≥3 months prior to randomization. Eligible pts have achieved a partial response or better (IMWG criteria) to DARA-based therapy, with a duration of response of ≥4 months. Pts must not have discontinued DARA due to a related adverse event or received prior treatment with carfilzomib. Pts will receive 20 mg/m2 carfilzomib IV on Day 1 of Cycle 1, escalated to 70 mg/m2 on Days 8 and 15; carfilzomib 70 mg/m2 will be administered on Days 1, 8, and 15 of each 28-day cycle thereafter. Dexamethasone 40 mg will be administered (IV or PO) QW for Cycles 1-9 and then on Days 1, 8 and 15 from Cycle 10 onwards. Pts in the D-Kd group will also receive DARA SC (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; Halozyme]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter. The primary endpoint is the rate of pts achieving a very good partial response or better. Secondary endpoints include overall response rate, rate of pts achieving complete response or better, progression-free survival, overall survival, overall minimal residual disease-negativity rate, time to next treatment, pharmacokinetics, and safety. Clinical trial information: NCT03871829 .