bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II trial evaluating combination pemetrexed and avelumab in patients with MTAP-deficient advanced urothelial cancer.
Authors: Shah Amishi Yogesh , Campbell Matthew T , Tidwell Rebecca , Siefker-Radtke Arlene O. , Goswami Sangeeta , Alhalabi Omar , Adriazola Ana Cecilia , Shaw Leah , Ye Yin , Chen Jianfeng , Yan Xinmiao , Wang Linghua , Gao Jianjun
Published: June 2022

TPS4612

Background: MTAP-deficiency occurs primarily due to homozygous loss in chromosome 9p21 and is seen in approximately 25% of urothelial cancers. MTAP-deficiency portends aggressive biology with poorer outcomes than in MTAP-proficient tumors; for example, in the IMvigor210 data, MTAP-deficient patients had median overall survival of 8.0 months, compared to 11.3 months in MTAP-proficient patients (p = 0.042). MTAP-deficient tumors lack salvage nucleotide synthesis pathways and thus are uniquely sensitive to anti-folate agents; however, in prior clinical work with pemetrexed in these tumors, responses are relatively short-lived. In-vivo data has suggested that pemetrexed can increase tumor infiltrating T-cells, macrophages, dendritic cells, and PD-L1 expression in MTAP-deficient tumors and decrease myeloid-derived suppressor cells (MDSCs). As such, it was postulated that sequential treatment with anti-folate chemotherapy (pemetrexed) and immune checkpoint inhibition (avelumab) would improve responses in MTAP-deficient urothelial cancer. Methods: A prospective phase II trial of patients with advanced MTAP-deficient urothelial cancer is being conducted under IRB-approved protocol NCT03744793. This study will enroll 25 patients at a single site (The University of TX, MD Anderson Cancer Center). Key eligibility criteria include patients with advanced MTAP-deficient urothelial cancer with measurable disease in second-line or beyond. MTAP-deficiency is confirmed with CLIA-approved IHC or NGS. Patients are stratified as being IO-pretreated versus IO-naïve. All patients receive a lead-in cycle of pemetrexed (500 mg/m2) followed by combination pemetrexed (500 mg/m2) and avelumab (10 mg/kg) IV every three weeks until disease progression, patient withdrawal, or unacceptable toxicity. Three biopsies per patient with tissue collection at trial baseline, on single agent pemetrexed, and on combination pemetrexed-avelumab are performed. The primary objective of this trial is to evaluate response rate with sequential pemetrexed and avelumab in MTAP-deficient urothelial cancer. Imaging response assessment is done via RECIST v1.1. Secondary objectives are to evaluate progression-free survival (PFS) and overall survival (OS), as well as to perform correlative studies evaluating the effect of this therapy on immune cells and tumor microenvironment. This correlative work includes but is not limited to evaluation of peripheral T-cells, tumor-infiltrating T-cells, macrophages, and MDSCs. Interim analyses for futility and safety occur in cohorts of 5 patients and are performed based on Bayesian sequential methods. Fifteen patients have been enrolled thus far. Clinical trial information: NCT03744793.
Subcutaneous nivolumab versus intravenous nivolumab in patients with previously treated, advanced, or metastatic clear cell renal cell carcinoma.
Authors: Chacon Matias Rodrigo , Cutuli Hernan J. , Bracarda Sergio , Maruzzo Marco , Bourlon Maria Teresa , Jacobs Carmel , Pérez-Valderrama Begoña , Magri Ignacio , Richardet Martin , Centkowski Piotr , Fu Simon Yuen Fai , Gurman Pablo , Konduri Srivani , Yu Zhuoxin , Vezina Heather , George Saby , Albiges Laurence
Published: June 2022

TPS4621

Background: Nivolumab (NIVO), a programmed death-1 immune checkpoint inhibitor, has demonstrated clinical efficacy across patients with different tumor types, including clear cell renal cell carcinoma (ccRCC), when administered via IV infusion. As an alternative to IV infusion, subcutaneous (SC) administration alleviates the need for IV ports, thereby lowering the risk of associated complications such as infections and phlebitis. SC formulation also reduces the time for dose preparation and administration, which may decrease overall treatment burden and reduce patient time in the clinic, benefiting patients and healthcare providers and improving overall healthcare resource utilization. SC-administered NIVO consists of NIVO co-formulated with the recombinant human hyaluronidase PH20 enzyme (NIVO + rHuPH20), which aims to increase the dispersion and absorption of NIVO within the SC space. SC NIVO + rHuPH20 was shown to be safe and well tolerated in a phase 1/2 study, warranting further investigation (Lonardi S et al. J Clin Oncol 2021;39(suppl 15):2575). Methods: CheckMate 67T is a multicenter, randomized, open-label, phase 3 study that will evaluate the noninferiority of SC NIVO + rHuPH20 versus IV NIVO in patients with advanced or metastatic ccRCC who have progressed after receiving ≤ 2 prior systemic treatment regimens. Key inclusion criteria are age ≥ 18 years, histologically confirmed advanced or metastatic ccRCC, measurable disease by RECIST v1.1 within 28 days prior to randomization, and a Karnofsky performance status ≥ 70. Key exclusion criteria are untreated symptomatic metastases to the central nervous system, other malignancy, autoimmune diseases, HIV-positive status with AIDS-defining infection within past year or current CD4 count < 350 cells/μL, other serious or uncontrolled disorders including severe, acute SARS-CoV-2 infection, and prior treatment with immune checkpoint inhibitors, other T-cell–targeting antibody drugs, or live attenuated vaccines within 30 days of first study treatment. At least 454 eligible patients will be randomized to receive SC NIVO + rHuPH20 or IV NIVO. The primary objectives are to demonstrate pharmacokinetic (PK) noninferiority of SC NIVO versus IV NIVO, as measured by time-averaged serum concentration over the first 28 days (Cavgd28) and trough serum concentration at steady state (Cminss) (co-primary endpoints). Secondary endpoints include objective response rate by blinded independent central review, additional PK parameters, safety, efficacy, and immunogenicity of SC NIVO and IV NIVO. This study is currently enrolling patients globally. Clinical trial information: NCT04810078.
Phase 3 VERACITY clinical study of sabizabulin in men with metastatic castration-resistant prostate cancer who have progressed on an androgen receptor targeting agent.
Authors: Dreicer Robert , Chu Franklin , Cahn David J , Getzenberg Robert H. , Rodriguez Domingo , Barnette K. Gary , Steiner Mitchell S. , Saltzstein Daniel R. , Tutrone Ronald F. , Shore Neal D.
Published: June 2022

TPS5102

Background: Sabizabulin is a first-in-class, oral agent that inhibits microtubule polymerization disrupting the cytoskeleton and arresting cellular proliferation. A Phase 1b/2 clinical study was conducted to establish the MTD and evaluate the preliminary efficacy in men with metastatic castrate resistant prostate cancer (mCRPC) who progressed on at least one androgen receptor targeting agent (ARTA). The most common AEs reported were mild to moderate diarrhea, fatigue, nausea, and vomiting with no clinically relevant neurotoxicity or neutropenia. In the Phase 1b/2, the median radiographic progression free survival for the 63mg dose (n = 55) was 11.4 months (range 6-36+ months) in the Phase 1b portion including responses > 2.75 years. The Phase 3 reformulation which had improved bioavailability is 32mg PO qd. Methods: VERACITY is an ongoing Phase 3 multicenter, randomized, active-control study designed to evaluate sabizabulin in the treatment of mCRPC who have progressed on at least one ARTA. Patients on the study will be chemotherapy naive. Subjects (n = 245) are being randomized in a 2:1 ratio to receive sabizabulin (32 mg/d oral) or active control (alternative ARTA) and will remain on study until radiographic progression-free survival (rPFS). Randomization will be stratified by: measurable disease vs bone-only disease and by prior exposure to ARTA (progressed on one vs more than one prior ARTA). The primary efficacy endpoint of the study is median rPFS. Secondary endpoints include: objective response rate (ORR), duration of objective response, overall survival and time to intravenous (IV) chemotherapy. The Phase 3, VERACITY registration clinical trial is current ongoing in approximately 45 clinical sites with enrollment anticipated to be completed in 2022 and with unblinded results presented in 2023 Based upon the Phase 1b/2 clinical trial, sabizabulin daily chronic oral dosing has a favorable safety profile, is feasible to administer chronically, and has significant and durable antitumor activity. mCRPC that has progressed following ARTAs and prior to taxane chemotherapy, remains an urgent unmet medical need for patients with advanced disease. Sabizabulin is an exciting first-in-class agent that may add to the armamentarium for the treatment of mCRPC following progression on ARTA’s. Clinical trial information: NCT04844749.
A phase III double blinded study of early intervention after radical prostatectomy with androgen deprivation therapy with darolutamide versus placebo in men at highest risk of prostate cancer metastasis by genomic stratification (ERADICATE).
Authors: Morgans Alicia K. , Chen Yu-Hui , Ferrari Anna C. C. , Tran Phuoc T. , Schaeffer Edward M. , Shevrin Daniel H. , Szmulewitz Russell Zelig , Boike Thomas , Dorff Tanya B. , Liu Glenn , Wagner Lynne I. , Carducci Michael Anthony
Published: June 2022

TPS5114

Background: Patients with high-risk scores by Decipher molecular testing after prostatectomy have a 5-year metastasis rate of 28% (Decipher 0.6-0.7) and 38% (Decipher > 0.7), likely due to micrometastatic disease. Clinical trials with intensified systemic treatment are warranted to increase cure rates and address this unmet need. Previous studies of adjuvant androgen deprivation therapy (ADT) in clinically identified high-risk disease have not demonstrated substantial benefit other than in men with lymph node positive disease. Darolutamide is a novel androgen receptor antagonist with demonstrated efficacy in improving metastasis-free survival (MFS) and overall survival (OS) in patients with non-metastatic castration-resistant prostate cancer, and OS in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Whether treatment with ADT and darolutamide can increase MFS versus ADT plus placebo in the adjuvant setting for men with molecularly identified high-risk prostate cancer is unknown. Methods: Patients with CAPRA-S scores ≥3 and a PSA < 0.2 after radical prostatectomy undergo Decipher testing provided by the trial. Eligible patients with high-risk Decipher scores (> 0.6) will be randomized to treatment with ADT with darolutamide or placebo for 12 months. Patients are stratified by intent to deliver adjuvant radiation and by baseline PSA (undetectable vs detectable but < 0.2 ng/mL). The primary endpoint is MFS defined by novel PET or conventional imaging. With a sample size of 810 patients, the trial has 80% power with one-sided alpha = 0.025 to detect a HR of 0.60 for the experimental arm vs control arm for the primary endpoint. Secondary endpoints include recurrence-free survival, event-free survival, and quality of life (FACT-P, FACT-Cog, and FACIT-Fatigue), overall survival, and other disease-related outcomes. Trial was activated on December 9, 2020, and is currently enrolling patients. Clinical trial information: NCT04484818.
A randomized trial on pelvic lymph node dissection versus no lymph node dissection at radical prostatectomy: Report of a trial in progress.
Authors: Benfante Nicole , Carroll Erin , Carruthers Jessica , Donahue Timothy F. , Eastham James Andrew , Ehdaie Behfar , Goh Alvin C. , Laudone Vincent Paul , Pietzak Eugene J. , Smith Robert , Vickers Andrew , Sjoberg Daniel D. , Scardino Peter T. , Touijer Karim A.
Published: June 2022

TPS5116

Background: The therapeutic benefit of pelvic lymph node dissection (PLND) in the surgical treatment of localized prostate cancer remains unproven. In this trial we aim to evaluate whether PLND reduces biochemical recurrence rates in clinically localized prostate cancer patients. We are presenting our experience in accrual during our first year of implementing this trial at Memorial Sloan Kettering Cancer Center. Methods: Patients without evidence of positive or suspicious pelvic lymph nodes on pre-operative imaging, and without prior pelvic radiation for prostate cancer are eligible. Following informed consent prior to radical prostatectomy, patients are enrolled onto the trial and surgeons are randomized using a cluster randomization. Surgeons are randomized to perform a PLND vs. no PLND for a 3-month period. Since our trial began accruing in July 2020, we have enrolled 366 patients (51 high risk, 286 intermediate risk, and 29 low risk) out of 996 eligible patients (37%) through January 2022. We have enrolled 168 patients in the PLND arm and 198 patients in the no PLND arm. Table 1 shows the breakdown of patient consent status in each risk group, by randomization assignment. At this stage in the accrual, we do not see evidence of consenting bias among PLND vs. no PLND randomization and risk group. We conclude that a single-center cluster randomized trial can accrue large numbers of patients in a short period of time, allowing for large scale trials to be completed. Currently, our trial is on track to complete accrual within our 5-year goal. Clinical trial information: NCT01407263. [Table: see text]
A phase 3, single arm, open-label study evaluating ovarian suppression following 3-month leuprolide acetate for injectable suspension in combination with endocrine therapy in premenopausal subjects with HR+, HER2-negative breast cancer (OVELIA).
Authors: Tooker Ryan , Hamilton Erika P. , Lynch Kerlin , Atkinson Stuart , Turncliff Ryan
Published: June 2022

TPS608

Background: In US clinical practice, GnRH agonists are widely used to suppress ovarian function in pre/perimenopausal patients with breast cancer that is moderate-to high-risk for recurrence. Despite extensive use of leuprolide acetate (LA) for ovarian suppression, regulatory approval for this indication has not been established in the US. Additionally, existing three month formulations may not reliably provide ovarian suppression, as demonstrated by escapes in estradiol (E2). An extended-release LA product with a 3-month dosing period specifically developed for ovarian suppression in patients with breast cancer could fill this unmet need. TOL2506 is a 3-month, extended-release formulation of 30 mg of LA. This combination of active drug and in situ polymeric extended release technology is expected to deliver higher exposure to drug than the currently available 3-month (22.5 mg) formulations of LA marketed for advanced prostate cancer and potentially reduce escapes in E2 over the dosing period. Methods: TOL2506A (OVELIA) is a phase 3, single arm, open-label study evaluating the effectiveness of TOL2506 to suppress ovarian function in premenopausal women with HR+, HER2-negative breast cancer. Approximately 250 subjects will be enrolled, with 30% aged 40 years or younger. Subjects must be premenopausal women, age 18-49, with a diagnosis of Stage I, II, or III HR+, HER2-negative breast cancer (ER > 1% and/or, PR > 1%, HER2-negative per ASCO CAP guidelines), who are candidates for ovarian suppression with endocrine therapy. For subjects receiving chemotherapy, premenopausal status will be determined, and confirmed by central lab hormone testing, prior to initiating chemotherapy. Male subjects with HR+, HER2-negative breast cancer may also be eligible, but will be evaluated for safety analyses only. Eligible subjects will enter the 48 week treatment period in 2 groups: those receiving tamoxifen concurrently with TOL2506 or those who initiate therapy with an aromatase inhibitor (AI; letrozole, anastrozole, or exemestane) beginning 6 weeks after the first administration of TOL2506, if E2 < 20 pg/mL has been achieved. After Week 12, subjects will be allowed to switch from receiving an AI to receiving tamoxifen or from tamoxifen to AI at the Investigator’s discretion. Subjects will receive 4 doses of TOL2506 every 12 weeks over the 48 week study duration. Achievement of ovarian suppression will be defined as ≥ 90% of subjects with luteinizing hormone (LH) levels < 4 IU/L at Week 6. Secondary endpoints include suppression of LH, E2 (< 20 pg/mL for tamoxifen cohort and < 2.72 pg/mL for AI cohort) and absence of menses at weeks 6, 12, 24, 36, and 48. Clinical trial information: NCT04906395.
TIRA study: A phase III, multicenter, randomized controlled study of toripalimab plus radical chemoradiotherapy with or without concurrent cisplatin in patients with high-risk locoregionally advanced nasopharyngeal carcinoma.
Authors: Xu Cheng , Ma Jun
Published: June 2022

TPS6101

Background: Patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) suffer a high risk of distant metastasis and require guideline-recommended multimodality therapy. However, cisplatin-based concurrent chemotherapy leads to a high incidence of severe toxicities and low patient compliance, consequently limiting survival improvement. Toripalimab, an immune checkpoint inhibitor targeting programmed cell death 1 (PD-1), has a novel anti-cancer mechanism and mild toxicity spectrum. Robust evidence showed that given toripalimab + gemcitabine-cisplatin (GP) chemotherapy regimen, the median progression-free survival could be markedly improved in patients with recurrent and metastatic NPC. Besides, PD-1 antibody + radiotherapy is also regarded as a promising therapeutic strategy due to the synergistic effect. Therefore, we hypothesized that the de-intensification strategy using toripalimab + induction chemotherapy (IC) followed by radiotherapy alone would obtain equivalent survival and low toxicity in patients with LA-NPC compared with toripalimab + IC followed by concurrent chemoradiotherapy. Methods: TheTIRA study is a multicenter, randomized, controlled, open-label, phase III study. Since August 2021, we have been recruiting high-risk LA-NPC patients (stage III-IVa, except T3-4N0M0 & T3N1M0) from 12 Chinese centers. Our target sample size is temporarily set at 494 patients with 247 for each arm. Patients will be 1:1 ratio randomized to the experimental or control arm. Patients in the experimental arm will receive induction-concurrent toripalimab (240 mg, d1, Q3W × 6 cycle) with IC (gemcitabine 1000 mg/m2, d1 & d8 + cisplatin 80 mg/m2, d1, Q3W × 3 cycle) + intensity-modulated radiotherapy (IMRT, 70 Gy in 33 fractions), and thereafter adjuvant toripalimab (240 mg, d1, Q3W × 11 cycle). Patients in the controlled arm will receive an additional concurrent cisplatin (100 mg/m2, d1, Q3W × 2 cycle). The primary endpoint is the 3-year failure-free survival. Secondary endpoints include 3-year overall survival, 3-year distant metastasis-free survival, 3-year locoregional recurrence-free survival, quality-of-life assessment according to the systems of the European Organization for Research and Treatment of Cancer and the Functional Assessment of Cancer Therapy, and safety profile. Exploratory analysis will be performed for potential biomarkers of survival prediction including PD-L1 expression and tumor-infiltrating lymphocytes. Clinical trial information: NCT04907370.
A phase II study evaluating the efficacy of niraparib and dostarlimab (TSR-042) in recurrent/metastatic head and neck squamous cell carcinoma.
Authors: Karivedu Vidhya , Riaz Muhammad Kashif , Mathews Maria , Kurtzweil Nicky , Monroe Ilaina , Romano Audrey , Wise-Draper Trisha Michel
Published: June 2022

TPS6105

Background: Despite improvement in outcomes with checkpoint (PD-1) inhibitors in some patients (pts) with recurrent and metastatic head and neck squamous cell carcinoma (RM HNSCC), overall survival (OS) remains poor, necessitating novel therapy combinations. Fanconi Anemia (FA) and FA-related DNA repair pathways alterations have been associated with cumulative tumor mutational burden (TMB) due to genomic instability. High TMB is associated with improved response to PD-1 inhibitors. DNA pathway repair mutations have been reported in 17% of sporadic HNSCC. Ataxia-Telangiesctasia Mutated (ATM) loss has been reported in 60% of human HNSCC biopsies and FA-related defects were reported in 15-21% of human HNSCC biopsies and cell lines. Poly (ADP-ribose) polymerase (PARP) inhibition has already demonstrated efficacy as a single agent in multiple cancers which harbor a DNA repair defect. Preclinical data also showed PARP inhibitor (PARPi) upregulates PD-L1 expression in cancer lines and animal models via inactivation of glycogen synthase kinase 3 (GSK3β). Importantly, blockade of PD-1 re-sensitized PARPi treated cells to induce T-cell mediated cytotoxicity. Combination of PARPi and anti-PD-1 therapy significantly increased therapeutic efficacy in vivo compared to single agent. Therefore, we hypothesized that the combination of a PARPi (niraparib) and PD-1 blockade (dostarlimab) in our ongoing phase II study would enhance overall response (OR) and survival in R/M HNSCC pts (NCT04313504). Methods: Eligible pts must have a confirmed histopathology of non-cutaneous RM HNSCC not amenable to local therapy, progressive disease (PD) after at least one line of platinum-based chemotherapy and/or immunotherapy, age>18, ECOG <2, no prior therapy with PARPi and adequate bone marrow, liver, and renal function. Seven of 14 pts have been enrolled in the first stage of the study. If 8 or more pts develop either stable disease (SD), partial (PR) or complete response (CR), 9 additional patients will be accrued for a total of 23 patients. Pts will receive 200 mg PO niraparib daily in 28-day cycles along with dostarlimab 500mg (Q3W) for 4 doses followed by 1000mg (Q6W) until PD or unacceptable toxicity. An interim analysis will be performed to assess efficacy and safety after 14 patients become evaluable. Tumor response will be assessed per RECIST v1.1. Primary endpoint is best OR including SD, PR, and CR; Secondary endpoints include adverse events determined by CTCAE v5.0, progression free survival and OS. Integrated tissue analysis includes DNA pathway repair defects and TMB. Additional exploratory analyses including peripheral and immune cell activation will be performed on tissue and plasma samples. Clinical trial information: NCT04313504.
A phase 1b/2 study of nanatinostat and valganciclovir in patients with advanced Epstein-Barr virus positive (EBV+) solid tumors and in combination with pembrolizumab in patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC).
Authors: Colevas A. Dimitrios , Siu Lillian L. , Lim Darren Wan-Teck , Gao Bo , Rojkjaer Lisa , Katkov Afton , Katz Yisrael , Ma Brigette
Published: June 2022

TPS6107

Background: Epstein-Barr virus (EBV) is linked to the development and pathogenesis of nasopharyngeal carcinoma (NPC). Most patients present with advanced stage disease at diagnosis (Li 2014); first-line chemoradiation is commonly followed by recurrence and poor prognosis emphasizing the need for new treatment options. Targeting EBV in NPC represents a novel therapeutic approach. EBV is predominantly latent in NPC; pre-clinical studies demonstrated that induction of the viral lytic phase by histone deacetylase inhibitors (HDACi) renders EBV+ tumor cells susceptible to the cytotoxic activity of ganciclovir (GCV) (Hui 2016). Nanatinostat (Nstat), a potent Class-I HDACi, induces the expression of the lytic BGLF4 protein kinase in EBV+ tumor cells, which activates the nucleoside analog GCV via phosphorylation. Phosphorylated GCV becomes incorporated into the cellular DNA causing chain termination and apoptosis. The all-oral combination of Nstat and valganciclovir (VGCV), a pro-drug of GCV, has demonstrated favorable safety and preliminary efficacy in a phase 1/2 study in patients with recurrent EBV+ lymphoma (NCT03397706). This phase 1b/2, open-label, multicenter study will evaluate the safety, tolerability, pharmacokinetics, and preliminary activity of Nstat + VGCV in patients with advanced EBV+ solid tumors. Additionally, the combination of pembrolizumab together with Nstat + VGCV will be evaluated in recurrent/metastatic NPC (RM-NPC) patients. NPC frequently exhibits high PD-L1 expression levels; however, PD-1 inhibitors resulted in limited response rates ranging from 20-30% in the RM-NPC setting. Methods: Phase 1b utilizes a 3+3 dose escalation design to determine the recommended Phase 2 dose (RP2D) of Nstat + VGCV in patients with EBV+ RM-NPC. In Phase 2, up to 60 patients with EBV+ RM-NPC will be randomized 1:1 to receive Nstat + VGCV at the RP2D with or without pembrolizumab to evaluate safety, tolerability, overall response rate, and potential pharmacodynamic markers of drug activity, including plasma EBV DNA levels. Additionally, patients with EBV+ solid tumors other than RM-NPC will receive Nstat + VGCV at the RP2D in a separate Phase 1b dose expansion cohort. Patients eligible for the phase 1b dose escalation and phase 2 will have EBV+ RM-NPC with 1-3 prior lines of platinum-based chemotherapy and no available curative therapies. Patients with advanced EBV+ non-NPC solid tumors (gastric cancer, lymphoepithelioma-like carcinoma, leiomyosarcoma) and no curative therapies are eligible for the phase 1b expansion cohort. All patients must have measurable disease per RECIST v1.1 and adequate bone marrow, liver, and renal function. Enrollment began in January 2022. Clinical trial information: NCT05166577.
NHS-Galleri Trial Design: Equitable study recruitment tactics for targeted population-level screening with a multi-cancer early detection (MCED) test.
Authors: Swanton Charles , Neal Richard D , Johnson Peter W. M. , Dur Christina Clarke , Hamilton Stephanie A , Zhang Nan , Kumar Harpal , Sasieni Peter
Published: June 2022

TPS6606

Background: Cancer is a leading cause of premature death globally. Early detection can reduce cancer mortality by reducing the number of cancers diagnosed at a late stage. A blood-based MCED test (Galleri) was developed that can detect cancer signals and predict cancer origin with a single blood draw. The NHS-Galleri trial is a randomized controlled trial (RCT) assessing the clinical utility of this MCED test in a targeted screening population alongside current screening programs. Screening adherence is lower among certain individuals (eg, those with lower socioeconomic status), despite healthcare being free at the point of access in England. NHS-Galleri utilizes innovative strategies to optimize equity in study recruitment, with the goal of enrolling a representative sample. Methods: This pragmatic, blinded RCT is currently enrolling 140,000 asymptomatic participants by inviting ̃1.3 million residents aged 50-77 in select postcodes of England via the NHS DigiTrials service. Regions were selected to include areas of high cancer mortality, socioeconomic deprivation, and ethnic diversity; eligible participants will be identified from these regions. A variety of methods are employed to enroll a representative study population (defined as including a reasonable number of participants from all socioeconomic statuses and all major ethnic minority groups). These methods include the use of mobile phlebotomy clinics that facilitate access in economically deprived areas, monitoring of participant representativeness by postcode with dynamic adjustment of enrollment, providing interpreters and wheelchair accessibility, and targeted local campaigns. Blood will be collected at 3 annual visits (baseline, year 1, year 2) unless cancer is diagnosed. After baseline blood collection, participants will be randomized 1:1 to the intervention (blood sample analyzed by the MCED test) or control (blood sample stored for potential future MCED testing) arm. Only participants in the intervention arm with “cancer signal detected” will have results returned and be referred for investigations and possible treatment. Participants in the intervention arm without “cancer signal detected” and all in the control arm will remain blinded and return for annual visits. All participants will be reminded to continue guideline-based screening and report unusual/concerning symptoms to a doctor. The primary study objective is a significant reduction in the absolute numbers of stage III & IV cancers diagnosed in the intervention versus control arm 3.5 years after randomization. Cancer-specific mortality will be assessed during trial follow-up. Exploratory endpoints include assessing the primary objective by participant age, gender, socioeconomic status, and ethnicity. Clinical trial information: ISRCTN91431511.
CELESTIMO: A phase III trial evaluating the efficacy and safety of mosunetuzumab plus lenalidomide versus rituximab plus lenalidomide in patients with relapsed or refractory follicular lymphoma who have received ≥ 1 line of systemic therapy.
Authors: Nastoupil Loretta J. , Morschhauser Franck , Scholz Christian W. , Bishton Mark , Yoon Sung-Soo , Giri Pratyush , Wei Michael C. , Knapp Andrea , Li Chi-Chung , Bottos Alessia , Li Haocheng , Purev Enkhtsetseg , Bartlett Nancy L.
Published: June 2022

TPS7588

Background: Despite significant progress with first-line immunochemotherapy, most patients with follicular lymphoma (FL) will eventually relapse with increasing refractoriness and decreasing duration of response to subsequent therapy lines (Rivas-Delgado et al. 2019). Mosunetuzumab (M) is a CD20xCD3 bispecific antibody that engages and redirects T-cells to eliminate malignant B cells (Sun et al. 2015). In an ongoing, pivotal Phase I/II trial of M monotherapy, patients with relapsed/refractory (R/R) FL who have received ≥2 prior treatment lines achieve deep and durable responses (NCT02500407; Budde et al. ASH 2021). Preliminary data from a Phase Ib study have suggested favorable safety and promising activity of M in combination with lenalidomide (Len), a potent immunomodulatory agent that has shown additive/synergistic activity with an anti-CD20 antibody in R/R indolent lymphoma (Leonard et al. 2019), in patients with R/R FL who have received ≥1 prior therapy (NCT04246086; Morschhauser et al. ASH 2021). The chemotherapy-free M-Len combination may represent a promising outpatient therapy option for future management of patients with R/R FL. The randomized, multicenter Phase III study has been initiated. Methods: CELESTIMO (NCT04712097) is a randomized, multicenter, open-label Phase III study evaluating the efficacy and safety of M-Len versus rituximab plus Len (R-Len) in patients with previously treated R/R FL. Patients must have histologically documented CD20+ FL (Grades 1–3a) requiring systemic therapy and have received ≥1 prior line of systemic therapy. Patients are randomized (1:1) to receive M-Len (M intravenously [IV] on Days [D] 1, 8 and 15 of Cycle [C] 1 [21-day cycle] and D1 of C2–12 [28-day cycles], plus Len orally [PO] on D1–21 of C2–12) or R-Len (R IV on D1, 8, 15 and 22 of C1 then on D1 of C3, 5, 7, 9, and 11, plus Len PO on D1–21 of C1–12 [all 28-day cycles]), and stratified by disease progression within 24 months of initial treatment (yes/no), number of prior lines of therapy (1 versus ≥2), and refractoriness to anti-CD20 therapy (refractory/non-refractory). The primary endpoint is progression-free survival (PFS) assessed by independent review committee; secondary endpoints include investigator-assessed PFS, complete and objective response, overall survival, and safety. Biomarkers predictive of response to M-Len and R-Len will also be investigated as exploratory endpoints. The study started recruitment in 2021 and plans to enroll ̃400 patients from approximately 16 countries and 150 sites globally. Clinical trial information: NCT04712097.
A phase I study of duvelisib in combination with oral azacitidine (CC-486) in relapsed lymphoid malignancies.
Authors: Saeed Hayder , Sahakian Eva , Maharaj Kamira Karen , Mo Qianxing , Zhang Ling , Makanji Rikesh J , Isenalumhe Leidy Lismeri , Gaballa Sameh , Chavez Julio C. , Shah Bijal D. , Bello Celeste M. , Pinilla-Ibarz Javier , Sokol Lubomir
Published: June 2022

TPS7594

Background: Phosphoinositide 3-kinase (PI3K) inhibitors have shown promising activity in lymphoid malignancies such as mature T cell lymphoma, diffuse large B cell lymphoma, and mantle cell lymphoma. Duvelisib’s PI3K-δ and PI3K-γ activity in T cell lymphoma is promising as a single agent (Horwitz, Koch et al. 2018). While the safety profile can generally be managed, certain autoimmune adverse events may limit its adaptation in clinical practice. Azacitidine, a pyrimidine nucleoside analog of cytidine, is active in T cell lymphoma (Saillard, Guermouche et al. 2017) as well as in DLBCL (Martin, Bartlett et al. 2018). Hypomethylators could enhance the activity of PI3K inhibitors through increasing PTEN expression (Spangle, Roberts et al. 2017), and upregulation of tumor suppressor genes (Zuo, Liu et al. 2011). Duvelisib’s immune mediated adverse events may be related to shifts in T cell differentiation towards Th17 phenotype and decreases in T reg differentiation that found to be more pronounced in patients with higher immune related toxicity (Gadi, Kasar et al. 2019). Studies have shown that T regs can be induced from Cd4+CD25- T cells using DNA methyltransferase inhibition with azacitidine (Fagone, Mazzon et al. 2018). Thus, the intermittent administration of azacytidine can potentially restore the balance by increasing T regs to decrease the autoimmune toxicity while maintaining Th17 phenotype that enhances tumor killing as shown in myelodysplastic syndrome (Jia, Yang et al. 2020). Methods: This is a 3+3 phase I dose escalation study designed to determine the maximum tolerated dose (MTD) of CC-486 in combination with duvelisib in patients with lymphoid malignancies. The MTD is defined as the highest dose with an observed incidence of dose limiting toxicity (DLT) in no more than one out of six patients treated at a particular dose level. Secondary endpoints include best overall response, disease control rate and duration of response. Exploratory end points will be biomarker driven with focus on the composition of different T cell compartments during the administration of the combination. Efficacy biomarkers will include measuring the phosphorylation of AKT in peripheral CD3+ T cells. Oral duvelisib will be given continuously with the dose escalation maintained during the first 2 cycles while CC-486 schedule will be 14 days on/14 days off. The first cohort of patients are enrolled, and are in the DLT testing period. Clinical trial information: NCT05065866.
Trial in progress: A phase 1b study evaluating the safety, tolerability, and preliminary anti-tumor activity of NT-I7 (efineptakin alfa), a long-acting human IL-7, post-tisagenlecleucel in subjects with relapsed/refractory large B-cell lymphoma.
Authors: Ghobadi Armin , Budde L Elizabeth , Galal Ahmed , Stermer Kristina , Austin TaShara Lynn , Fan Jean , DiPersio John F.
Published: June 2022

TPS7596

Background: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy with tisagenlecleucel (Kymriah) is standard of care (SOC) for patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). CAR-T expansion is a strong predictor of response to this therapy. NT-I7 (efineptakin alfa) is a first in-class, long-acting human IL-7 previously shown clinically in solid tumor studies to increase the number and functionality of T-cells in peripheral blood and within tumors. In a CD19+ lymphoma xenograft mouse model that received anti-CD19 universal CAR-T infusion, NT-I7 treatment prolonged survival and enhanced CAR-T gene expression of functional markers, proliferation, persistence, and tumor killing. We hypothesize that NT-I7 administration after tisagenlecleucel SOC for subjects with r/r LBCL may increase expansion and persistence of CAR-T, leading to increased tumor response rate and improved clinical outcomes without safety concerns. Methods: This phase 1b study consists of a dose-escalation phase followed by a dose expansion. In dose escalation, subjects receive tisagenlecleucel infusion on Day 0 and a single dose of NT-I7 on Day 21, at 7 dose levels (DLs 1-7): 60, 120, 240, 360, 480, 600, and 720 μg/kg. DLs 1 and 2 will enroll 1 subject each, followed by a 3+3 design for the remaining DLs. Up to 42 subjects will be enrolled for the dose-escalation phase and up to 15 subjects in the dose-expansion phase, treated at the recommended phase 2 dose (RP2D). Eligible subjects are ≥18 years of age with biopsy-proven diagnosis of r/r LBCL after ≥2 lines of systemic therapy, including diffuse LBCL (DLBCL) not otherwise specified (NOS), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Subjects must be eligible for tisagenlecleucel as SOC. Subjects who have received prior CD19-directed therapy are ineligible. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) and/or RP2D for NT-I7 with this regimen. Secondary objectives are to explore the anti-tumor activity of this regimen for r/r LBCL. The effect of NT-I7 after tisagenlecleucel infusion on the safety profile regarding Grade ≥3 Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) will also be evaluated. Exploratory objectives are to assess pharmacokinetic parameters of tisagenlecleucel with NT-I7 administration, and correlative studies will evaluate the effects of this regimen not limited only to the expansion of lymphocytes and serum cytokines. As of January 3, 2022, 2 subjects have received NT-I7 in the dose-escalation phase at DL1 and DL2. Clinical trial information: NCT05075603.
Trial in progress: A phase 2 study of sotorasib as first-line treatment in patients with stage IV non–small cell lung cancer (NSCLC) whose tumors harbor a KRAS p.G12C mutation (CodeBreaK 201).
Authors: Arbour Kathryn Cecilia , Khurana Monica , Dai Tian , Skoulidis Ferdinandos
Published: June 2022

TPS9150

Background: Chemo-immunotherapy regimens represent a standard of care for the first-line treatment of metastatic NSCLC, yet clinical outcomes in patients bearing tumors that lack PD-L1 expression [PD-L1 Tumor Proportion Score (TPS) < 1%)] or harbor a serine/threonine kinase 11 ( STK11) mutation remain poor. Sotorasib is a selective, irreversible small molecule KRASG12C inhibitor that is approved for the treatment of patients with locally advanced or metastatic KRAS p.G12C-mutated NSCLC following failure of at least one prior line of systemic therapy and has previously demonstrated robust antitumor activity in subgroups of KRAS p.G12C mutant NSCLC with PD-L1 TPS <1% and/or STK11 co-mutations. We hypothesized that sotorasib may represent an effective first-line therapy for subgroups of NSCLC patients who may have suboptimal chemo-immunotherapy outcomes and a high unmet clinical need. Methods: This phase 2, open-label, global study is designed to evaluate the efficacy and safety of sotorasib (960 mg or 240 mg daily) as first-line treatment in approximately 170 patients with KRAS p.G12C-mutated, metastatic NSCLC with PD-L1 TPS <1% as determined by immunohistochemical assay and/or presence of STK11 mutation as determined by next-generation sequencing (NGS). Key eligibility criteria include patients with untreated metastatic NSCLC without active brain metastases. Patients will be stratified by known presence of STK11 mutation. The primary endpoint is objective response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary endpoints include disease control, duration of response, time to response, progression-free survival per RECIST 1.1, overall survival, safety and tolerability, and pharmacokinetic profile. Enrollment began in January 2022 and is ongoing. Contact Amgen Medical Information for more information. Clinical trial information: NCT04933695.
Additional chemotherapy for EGFRm patients with the continued presence of plasma ctDNA EGFRm at week 3 after start of osimertinib first-line treatment (PACE).
Authors: Stratmann Jan Alexander , Acker Fabian , Aspacher Lukas , Alt Juergen , Althoff Friederike C , Heinzen Sophie , Gökbuget Nicola , Müller Ina , Reiser Lena , Hehn Sina , Serve Hubert , Mänz Martin , Meyer Frauke , Sebastian Martin
Published: June 2022

TPS9157

Background: Epidermal growth factor receptor (EGFR) – mutated non-small cell lung cancer (NSCLC) is susceptible to EGFR targeting tyrosine kinase inhibitors (TKI), such as the third generation TKI osimertinib. However, response rate and duration vary between patients. Among others, the specific subtype of EGFR-mutation, its co-occurrence with other genetic alterations, and the detection of phosphorylated EGFR (pEGFR) in the plasma, and its clearance upon treatment were previously identified as markers that predict therapy response. A high proportion of patients with early (3-6 weeks after start) pEGFR clearance from plasma show impressive survival upon single-agent TKI. However, failure to achieve early clearance upon Osimertinib is associated with unfavorable outcome. For these patients, treatment concepts are lacking. Here, we report about the initiation of a clinical trial that evaluates the combination of EGFR-directed TKI and platinum-based chemotherapy as an early treatment escalation strategy for this high-risk patient population. Methods: PACE is a prospective multicenter single-arm investigator-initiated phase II trial. Patients with NSCLC harboring L858R or del19 EGFR mutation, who are treated with first-line Osimertinib are subjected to liquid biopsy-based early response assessment three weeks after start of therapy. Failure to clear pEGFR from plasma at this time point triggers treatment escalation with the addition of platinum-based doublet chemotherapy to the Osimertinib treatment. The primary outcome measure of the trial is progression-free survival (PFS), with the objective to assess the efficacy of biomarker-driven escalation of osimertinib therapy with a combination platinum-based regimen. Secondary outcome measures are the overall response rate (ORR), overall survival (OS), and the Quality of life (QLQ-C30, CTCAE-PROs) of the treated patients. In exploratory analyses, we will assess whether specific patterns of co-mutations are associated with early treatment failure (upon TKI) and pEGFR persistence. Fig. 1 illustrates the trial concept. A sample of 46 subjects achieves 80% power at a 0.05 significance level to detect a PFS of 14.4 months in the experimental treatment group when the PFS of the historic control group is 9.1 months; a total of 400 patients need to be screened within the national Network Genomic Medicine. Enrollment started in 12/2021. The clinical trial is supported by AstraZeneca and Guardant. EudraCT registration number: 2019-004757-88 .
ARTISTRY-6: Nemvaleukin alfa monotherapy in patients with advanced mucosal and cutaneous melanoma.
Authors: Weber Jeffrey S. , Carvajal Richard D. , Hamid Omid , Kim Seung Tae , Kim Miso , Sullivan Ryan J. , Lee Dae Ho , Mehmi Inderjit , Grewal Jaspreet Singh , Lee Hyo Jin , Dudek Arkadiusz Z. , Du Yangchun , Desai, MD Monali , Wang Yan , Mayo Carlos Alberto , Middleton Mark R.
Published: June 2022

TPS9609

Background: Despite improved outcomes for melanoma patients with the introduction of checkpoint inhibitors (CPIs), ̃50% of patients do not respond. A subset of responders ultimately progress and have limited treatment options, underscoring a high unmet need for novel treatments with durable benefit. Patients with mucosal melanoma exhibit response rates and progression-free survival times ̃2 times lower than those with cutaneous melanoma. Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds the intermediate-affinity interleukin-2 receptor complex to preferentially activate CD8+ T and NK cells with minimal expansion of regulatory T cells. Nemvaleukin has been granted Orphan Drug designation for the treatment of mucosal melanoma by the FDA. In ARTISTRY-1, the intravenous (IV) recommended phase 2 dose (RP2D) of 6 µg/kg nemvaleukin monotherapy demonstrated durable antitumor activity in patients with advanced melanoma, including mucosal melanoma, previously treated with a CPI. In ARTISTRY-2, the subcutaneous (SC) RP2D of 3 mg q7d was identified demonstrating pharmacodynamic effects consistent with IV delivery. Data support further evaluation of nemvaleukin monotherapy among patients with advanced mucosal and cutaneous melanoma. Methods: ARTISTRY-6 is a phase 2, global, multicenter, open-label study. Eligible patients have had prior treatment with an anti–PD-(L)1 therapy with or without anti–CTLA-4 therapy and have an ECOG performance status of 0 or 1 and adequate hematologic reserve and hepatic and renal function. Patients with advanced cutaneous (Cohort 1) and mucosal (Cohort 2) melanoma will receive nemvaleukin at the SC and IV RP2D, respectively. Patients will receive nemvaleukin until progression or intolerable toxicity. The primary objective is to evaluate the antitumor activity of nemvaleukin monotherapy defined by overall response rate. Additional objectives include the evaluation of safety, health-related quality of life, predictive biomarkers, pharmacokinetics, immunogenicity, and pharmacodynamic effects. Clinical trial information: NCT04830124.
Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO
Authors: Rossini Daniele , Antoniotti Carlotta , Lonardi Sara , Pietrantonio Filippo , Moretto Roberto , Antonuzzo Lorenzo , Boccaccino Alessandra , Morano Federica , Brugia Marco , Pozzo Carmelo , Marmorino Federica , Bergamo Francesca , Tamburini Emiliano , Passardi Alessandro , Randon Giovanni , Murgioni Sabina , Borelli Beatrice , Buonadonna Angela , Giordano Mirella , Fontanini Gabriella , Conca Veronica , Formica Vincenzo , Aglietta Massimo , Bordonaro Roberto , Aprile Giuseppe , Masi Gianluca , Boni Luca , Cremolini Chiara
Published: June 2022

PURPOSE

To verify whether the intensification of the upfront chemotherapy backbone with a modified schedule of modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) increases the activity of fluorouracil, leucovorin, and oxaliplatin when both regimens are combined with panitumumab as initial treatment for RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC).

METHODS

TRIPLETE was a prospective, open-label, phase III trial in which previously untreated patients with unresectable RAS and BRAF wt mCRC were randomly assigned 1:1 to modified FOLFOX/panitumumab (control group) or mFOLFOXIRI/panitumumab (experimental group) up to 12 cycles, followed by fluorouracil/-leucovorin/panitumumab until disease progression. The primary end point was objective response rate (ORR) according to RECIST 1.1. Hypothesizing an ORR of 60% in the control group, 432 cases provided 90% power to a two-sided chi-square test for heterogeneity with a two-sided alpha error of .05 to detect ≥ 15% differences between arms (ClinicalTrials.gov identifier: NCT03231722 ).

RESULTS

From September 2017 to September 2021, 435 patients were enrolled (control group/experimental group: 217/218) in 57 Italian sites. One hundred sixty (73%) patients treated with mFOLFOXIRI plus panitumumab and 165 (76%) patients treated with modified FOLFOX plus panitumumab achieved RECIST response (odds ratio 0.87, 95% CI, 0.56 to 1.34, P = .526). No differences in early tumor shrinkage rate (57%/58%, P = .878) and deepness of response (median: 48%/47%, P = .845) were reported, nor in R0 resection rate (25%/29%, P = .317). No significant difference between arms was reported in terms of progression-free survival (median progression-free survival: 12.7 in the experimental group v 12.3 months in the control group, hazard ratio: 0.88, 95% CI, 0.70 to 1.11, P = .277).

CONCLUSION

The intensification of the upfront chemotherapy backbone in combination with panitumumab does not provide additional benefit in terms of treatment activity at the price of increased gastrointestinal toxicity in patients with RAS and BRAF wt mCRC.