bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 2 study to evaluate palbociclib in combination with irinotecan and temozolomide in pediatric patients with recurrent or refractory Ewing sarcoma.
Authors: Laetsch Theodore Willis , Janeway Katherine A. , Hawkins Douglas S. , Juszczak-Kosela Katarzyna , Muscal Jodi Ann , Collier Anderson B.
Published: June 2022

TPS11583

Background: Palbociclib (PD-0332991) is a highly selective, reversible, small molecule inhibitor of cyclin-dependent kinases (CDK) 4 and 6, administered orally. Functional dependence of Ewing Sarcoma (EWS) cell lines and tumor xenografts on Cyclin D1/CDK4 via genetic knockdown has shown both Cyclin D1 and CDK4 as critical dependencies for EWS cell line proliferation. The phase 1 portion of the study established the recommended Phase 2 dose (RP2D) with two chemotherapy backbones in children with solid tumors. The Phase 2 portion of the study now enrolls patients with EWS. The primary objective of this portion of the study is to determine whether the addition of palbociclib to irinotecan (IRN) and temozolomide (TMZ) will prolong event-free survival (EFS) of pediatric and young adult patients with recurrent or refractory EWS. Methods: Patients with recurrent or refractory EWS are randomized 2:1 to receive either palbociclib in combination with IRN and TMZ or IRN and TMZ alone. Randomization is stratified by type and time of disease recurrence (primary refractory or 1st recurrence <2 years vs. 1st recurrence ≥2 years or 2nd or greater recurrence). The primary efficacy endpoint is EFS per investigator assessment. Secondary efficacy endpoints include objective response, progression-free survival and overall survival. An interim futility analysis will be conducted to allow for early stopping of the study due to futility/no signal of activity based on the primary endpoint of EFS. Safety and planned interim efficacy data will be assessed by an Independent Data Monitoring Committee (DMC). Key eligibility criteria include: recurrent or refractory EWS with evaluable disease, no known bone marrow metastases, histopathological confirmation of EWSR1-ETS or FUS-ETS rearrangement or availability of formalin fixed paraffin embedded (FFPE) tumor tissue sample for central testing, age ≥2 and <21 years at the time of study entry. Treatment intervention: Patients randomized to palbociclib with IRN and TMZ treatment arm will receive palbociclib at the RP2D of 75 mg/m2 orally (either as a capsule or oral solution) once daily on Days 1-14 of each 21-day treatment cycle. TMZ will be administered orally once daily at 100 mg/m2 on Days 1-5 (intravenously (IV) if patient cannot swallow the TMZ capsule). IRN will be administered IV at 50 mg/m2 on Days 1-5. Patients randomized to the chemotherapy only treatment arm will receive IRN and TMZ at the same doses on Days 1-5 of the 21-day treatment cycle. Treatment will continue until disease progression, patient and/or legal guardian refusal, unacceptable toxicity , or up to 24 months of treatment, whichever occurs first. The Phase 2 enrolment has been initiated and 1/75 patients has been enrolled as of Jan 2022. Clinical trial information: NCT03709680.
A phase II study, with a safety lead-in, to evaluate ATX-101, a peptide drug targeting PCNA, in advanced dedifferentiated liposarcoma and leiomyosarcoma.
Authors: Bose Sminu , Ingham Matthew , Singh-Kandah Shahnaz V. , Magana Wendy , Schwartz Gary K.
Published: June 2022

TPS11587

Background: Soft tissue sarcoma (STS) is a heterogeneous malignancy of mesenchymal origin; leiomyosarcoma (LMS) and liposarcoma (LPS), two of the most common adult STS, are treated with first-line chemotherapy with objective response rates (ORRs) of 15-20%. There is an urgent need for novel therapeutics. ATX-101 is a small peptide comprised of a novel human AlkB homolog 2 proliferating cell nuclear antigen (PCNA) interacting motif termed APIM coupled to cellular and nuclear delivery domains. Via APIM, PCNA interacts with many cellular proteins important in the cellular stress and DNA damage responses, as well as intracellular signaling, apoptosis, metabolism, and anti-tumor immunity. In preclinical studies, ATX-101 demonstrated single-agent activity and potentiated other cytotoxic and targeted agents across multiple cancer models in vitro and in vivo, including LMS and LPS. In a phase I safety and pharmacokinetic study in solid tumors, ATX-101 was well tolerated and demonstrated prolonged disease stabilization in patients (pts) with heavily pretreated malignancies. This study will evaluate preliminary efficacy and further establish the safety profile of ATX-101 in advanced LMS and LPS. Methods: This is a single-arm, open-label, Simon 2-stage, phase II clinical trial of ATX-101 in pts with advanced LMS and LPS. Eligible pts have ECOG PS ≤2, progression on ≥1 prior line of therapy and disease measurable by RECIST v1.1 and amenable to image-guided biopsy. Pts receive ATX-101 60 mg/m2 IV weekly in continuous 21-day cycles. The 1° endpoint is progression free rate at 12 weeks (PFR12). A Simon 2-stage design is used to evaluate for improvement in PFR12 of ≤ 30% (null hypothesis) versus ≥ 55% (alternative hypothesis). The design calls for 34 pts with a safety lead-in among the first 10 pts enrolled. If 15/34 meet the PFR12 endpoint, the treatment is promising. This design yields 85% power and 1-sided type I error of 5%. 2° endpoints include progression free survival, ORR, and safety. 10 pts undergo tumor biopsies pre-treatment and during cycle 2. Tissue is used for correlative analysis interrogating ATX-101’s effects on the immune microenvironment through multiplex immunohistochemistry, DNA damage response through whole exome sequencing/RNAseq to evaluate for alterations in HR pathway component genes, and intracellular signaling pathways by Western blot for AKT/mTOR components. The study opened to accrual 12/2021. Clinical trial information: NCT05116683.
A phase 1b lead-in to a randomized phase 2 trial of lurbinectedin plus doxorubicin in leiomyosarcoma (LMS).
Authors: Cote Gregory Michael , Choy Edwin , Thornton Katherine Anne , Mazzola Emanuele , Bouberhan Sara , Merriam Priscilla , Wagner Andrew J. , Morgan Jeffrey A. , Haddox Candace L. , Oza Jay , Demetri George D. , George Suzanne
Published: June 2022

TPS11592

Background: Single agent or combination chemotherapy regimens, typically including doxorubicin or gemcitabine, represent standard of care options for first- and second-line therapy in patients (pts) with metastatic LMS. However, response rates (ORR) and progression-free (PFS)/overall survival (OS) remain poor. Lurbinectedin (PharmaMar S.A. and Jazz Pharmaceuticals) uniquely binds DNA, inducing DNA double strand breaks leading to apoptosis and delaying progression through phase S/G2 of the cell cycle. Lurbinectedin is a novel structural analog of trabectedin with improved toxicity profile, potency, and pharmacokinetics. In a prior pilot study, we showed that the combination of lurbinectedin and doxorubicin (L+D) was safe, with early signs of clinical activity, particularly in LMS. Thus, we designed this investigator-initiated/investigator-sponsored phase 1b lead-in to optimize doses of L+D, to be followed by a randomized (1:1) phase 2 study of L+D versus doxorubicin monotherapy in anthracycline-naïve LMS. Methods: Pts age > 18 years with locally advanced or metastatic, unresectable LMS (non-GIST soft-tissue sarcoma histologies allowed in Phase 1b), without prior anthracycline or lurbinectedin/trabectedin, ECOG PS < 3, measurable disease by RECIST 1.1, and normal organ function, are eligible. Phase 1b dosing will include a fixed dose of lurbinectedin and two dose levels of doxorubicin. The Phase 1b lead-in follows a standard 3+3 design where dose escalation will occur if 0/3 or 1/6 patients experience a dose-limiting toxicity (DLT). Tumor assessments are conducted every two cycles. Once the recommended phase 2 dose (RP2D) is confirmed, Phase 2 will be initiated. Fifty pts will be randomized 1:1 including doxorubicin +/- lurbinectedin. Randomization will be stratified by uterine v. non-uterine origin of LMS. Pts progressing on single agent doxorubicin will be allowed to cross over to lurbinectedin monotherapy. The Phase 2 primary endpoint is PFS. Secondary endpoints include disease control rate, ORR, OS, PFS2 (for doxorubicin monotherapy patients who cross to lurbinectedin monotherapy). Archival tumor, germline DNA, and ctDNA will be collected for correlative studies exploring genomic markers of sensitivity/resistance. We will provide respective point estimate along with 90% confidence interval for each of the arms. Log-rank test will be performed to test the difference in survival (both PFS and OS) between groups. Regression analyses of survival data will be based on the Cox proportional hazards model. The first pt in dose-level 1 of the Phase 1b lead-in was enrolled in February 2022. Clinical trial information: NCT05099666.
Screening for high frequency malignant disease (SHIELD).
Authors: NGUYEN HA , Raymond Victoria M. , Vento-Gaudens Erika , Marino Enrique , Lang Kathryn , Eagle Craig
Published: June 2022

TPS1602

Background: Implementation of asymptomatic cancer screening has yielded positive impacts on global cancer mortality rates. However, significant screening adherence gaps exist. A blood-based multi-cancer screening test with clinically significant performance in cancers where early detection and intervention can save lives, can address adherence gaps, especially by reducing access barriers inherent to current screening options. Effective evaluation of such a test in screen relevant populations requires studies designed to enroll individuals across multiple cancer types, taking into account prevalence rates for the cancers being evaluated, allowing for overlapping screen-eligible populations, and ensuring representation of individuals from diverse ethnicities and geographies. Methods: SHIELD (Screening for High Frequency Malignant Disease; NCT# 05117840) is a prospective, observational, multi-center basket study ongoing in the United States and Europe uniquely designed to recruit individuals across multiple cancer types. The study’s primary objective is to evaluate the performance of a blood-based multi-cancer screening test (GuardantLUNAR-2, Guardant Health, USA) to detect cancer in screen-relevant individuals as compared to the reference standard cancer screening modality. The study will recruit eligible individuals into multiple separate cohorts with specified pathways for cancer screening. Within each cohort, eligible individuals consent to whole blood collection within 90-days of the standard of care screening method. Clinical diagnoses, including the diagnosis of cancer, are made per standard of care. Primary outcomes are sensitivity, specificity, negative predictive value, and positive predictive value of the test as compared to the standard of care screening modality. Secondary outcome is the number of screen-detected cancers, early- (stage I/II) and late-stage (stage III/IV), per 1000 screened individuals. Follow-up continues for 24 months with outcomes collected at one and two-years to investigate the possibility of incidental non-screen relevant cancer cases and interval screen-relevant cancer cases that had not reached clinical threshold for detection at initial screening. Additional cancer specific follow-up is designed per cohort. The first cohort to enroll screen-eligible individuals, cohort A, is focused on those who meet guideline criteria for lung cancer screening with low dose CT. Additional cancer-risk cohorts will begin enrolling as the study expands and are designated cohort B, C, etc. Cohort A: Eligibility criteria are aligned with lung cancer screening guidelines – age 50-80 years with > 20 pack-year smoking history who are current smokers or have quit < 15 years prior, without a cancer history, preinvasive lung lesions, or current treatment for pneumonia. Cohort A enrollment, targeting 9,000 subjects over 24 months at up to 120 global sites, began in January 2022. Clinical trial information: NCT05117840.
A phase Ia/Ib study of intrathecal deferoxamine in patients with leptomeningeal metastases.
Authors: Wilcox Jessica , Modelevsky Lisa R. , Thomas Tiffany , Cremers Serge , Young Robert J. , Reiner Anne S. , Panageas Katherine , Yu Helena Alexandra , Boire Adrienne Ann
Published: June 2022

TPS2074

Background: Leptomeningeal metastases (LM) represent an aggressive form of advanced cancer with few durable therapeutic options. One of the principal barriers in treating LM is the paucity of knowledge on cancer cell survival and proliferation within the nutrient-sparse cerebrospinal fluid (CSF). Single-cell RNA sequencing of patient-derived CSF has identified that cancer cells in the spinal fluid employ the single iron-binding transporter and receptor system, lipocalin-2/SLC22A17, to gather sparse iron to sustain their metabolic needs. This phenotype is recapitulated in preclinical mouse models of LM. Depletion of CSF iron via intracisternal administration of deferoxamine, a parenteral iron chelator, dramatically reduced LM growth and significantly prolonged survival in preclinical models. Exploiting LM iron dependency using intrathecal deferoxamine (IT-DFO) represents a novel therapeutic approach for patients with LM. Methods: This is a prospective, open-label, single center phase Ia dose escalation study of IT-DFO in patients with LM from any solid tumor malignancy to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), followed by a phase Ib dose expansion of IT-DFO at the RP2D in patients with LM from non-small-cell lung cancer (NSCLC). Eligibility criteria include newly diagnosed or recurrent LM identified by magnetic resonance imaging (MRI), positive CSF cytology, and/or elevated CSF circulating tumor cells (CTCs), age ≥ 18 years, Karnofsky Performance Status ≥ 60, and life expectancy ≥ 8 weeks. All patients will receive IT-DFO in 28-day cycles at a frequency of twice weekly (cycle 1), once weekly (cycle 2), and once every two weeks (cycle 3+). Patients will be monitored for LM progression by neurological examination, neuraxial MRI, and CSF cytology as per modified Response Assessment in Neuro-Oncology LM criteria. Phase Ia will involve a modified accelerated titration over 9 dosing cohorts (IT-DFO dose range 10mg to 495mg) with monitoring for dose-limiting toxicities until the MTD is reached. Phase Ib will further explore the safety of IT-DFO at the RP2D in 20 patients with NSCLC LM. Secondary objectives include the determination of pharmacokinetic and pharmacodynamic properties of IT-DFO and its metabolite, ferrioxamine, in the CSF and serum (phase Ia/Ib), and efficacy outcomes (phase Ib) including LM-objective response rate, LM-clinical benefit rate, LM-duration of response, LM-progression-free survival, and overall survival. Exploratory analyses will prospectively correlate CSF CTC enumeration with treatment response and characterize the impact of IT-DFO on cancer cell metabolism, resistance pathways, and the CSF immune microenvironment. Clinical trial information: NCT05184816.
A randomized phase II study of anlotinib combined with STUPP versus STUPP alone in patients with newly diagnosed glioblastoma (GBM).
Authors: Chen Yuan yuan Yuan , Dong Baiqiang , Chen Zhongping
Published: June 2022

TPS2079

Background: Postoperative with radiotherapy, and concomitant and up to 6 cycles of maintenance temozolomide (TMZ) chemotherapy (STUPP regimen) is now the standard treatment for newly diagnosed GBM, while the effectiveness is limited. Anlotinib is a novel, multi-kinase inhibitor against both tumor angiogenesis and tumor cell proliferation with encouraging findings in preclinical GBM models. Our previous single-arm study (NCT04119674) showed that the addition of anlotinb to STUPP exhibited promising progression-free survival (PFS) in patients with GBM. Therefore, a phase II trial was designed to assessed the efficacy and safety of anlotinib with the STUPP regimen. Methods: This is a multicenter, randomized, controlled, phase II superiority trial. Approximately 150 patients will be randomly assigned 1:1 to receive TMZ-based radiochemotherapy with anlotinib or TMZ-based radiochemotherapy with placebo. All patients will receive radiotherapy (fractionated focal irradiation in daily fractions of 1.8–2.0 Gy given 5 days per week for 6 weeks, for a total of 54–60 Gy) concurrently with TMZ (75 mg/m2 QD) and anlotinib (10 mg QD, d1–14/3wks) or placebo. Anlotinib or placebo is administrated during the 28-day treatment break. Adjuvant therapy start four weeks after radiotherapy completion, including six cycles of TMZ (150–200mg/m2, d1–5/4wks) and eight cycles of anlotinib (10 mg QD, d1–14/3wks) or placebo. Patients who complete adjuvant therapy are administrated anlotinib or placebo continuously until the disease progressed or unacceptable toxic effects developed. Eligibility criteria include histologically confirmed newly diagnosed GBM and a World Health Organization (WHO) performance status ≤ 2. Additional inclusion criteria include patients between 18 and 75 years old with adequate wound healing of craniotomy or biopsy; adequate hematologic, hepatic, and renal function; acceptable blood coagulation levels; and the stable or decreasing usage of glucocorticoid doses within 5 days before randomization. Exclusion criteria include potentially fatal intracranial hemorrhage on magnetic resonance imaging (MRI); tumors located only in the brainstem; prior chemotherapy or radiotherapy administered for GBM; and IDH1/2 mutation. The primary objective of this study is to compare PFS accessed by Independent Review Committee in patients receiving anlotinib in addition to standard treatment with patients receiving standard treatment only. Secondary endpoints include overall survival (OS), PFS accessed by investigators, overall response rate (ORR), severity and frequency of AEs (CTCAE V5.0), and quality of life (QOL). The disease control rate (DCR) and duration of response (DOR) will also be explored. Clinical trial information: NCT04959500. Research Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd .
A phase I/IIa, open-label, multicenter, non-randomized clinical trial to assess the safety and efficacy of CYNK-001 in combination with recombinant human interleukin 2 in adults with recurrent resection eligible IDH1 wild-type glioblastoma (GBM).
Authors: Bota Daniela Annenelie , Badie Behnam , Heimberger Amy B. , Majd Nazanin , Awadalla Mark S. , Colerangle John , He Shawn , Koppisetti Sharmila , van der Touw William , Hariri Robert , Pecora Andrew L
Published: June 2022

TPS2080

Background: CYNK-001 is a CD56+CD3- enriched, off-the-shelf, allogeneic natural killer (NK) cell product expanded from placental CD34 cells. CYNK-001 exhibits in vitro cytotoxicity against patient-derived GBM cell lines and secretes cytolytic cytokines during co-culture with cancer cells. CYNK-001 administered via the intracranial (IC) route exhibited in vivo antitumor activity in a U-87MG orthotopic mouse model. Methods: A Phase I/IIa clinical trial is enrolling IDH1 wild-type GBM patients at first or second recurrence with contrast-enhancing measurable disease (per RANO criteria) who are candidate for surgical resection. Screening MRI scans for inclusion are performed within 14 days prior to Day -5 lymphodepletion with Cyclophosphamide 900mg/m2 and fludarabine 30mg/m2 plus mesna. Using a standard 3+3 dose escalation schema, patients will receive the first cycle of CYNK-001 intravenously (IV) at an initial dose of 2.4 x109 cells on Days 1, 8 and 15 after lymphodepletion. Cell supportive IL-2 at 6M IU administered SQ on Days 1, 3, 5, 8, 10, 12, and 15 within 3 hours prior to CYNK-001 IV infusion where applicable. Cycle 2 begins with surgical resection on Day 22 in which CYNK-001 is administered directly into the tumor cavity wall at an initial dose of 100 x106 NK cells and an Ommaya catheter placement. Subsequent CYNK-001 IC administrations via the Ommaya are on days 29 and 36 with 6M IU IL-2 SQ. DLT is evaluated for all dosing cohorts from day 1 to 7 days post last dose of cycle 2. Once a maximum tolerated dose is identified, a safety lead-in cohort with an additional 3 cycles of CYNK-001 IC will be administered prior to initiating the Phase IIa portion of the study. Endpoints: The primary endpoint is dose-limiting toxicity for the Phase I analysis and 6-month progression free survival post tumor resection for the Phase IIa component. Post-resected tumor tissue will be characterized for effector immune cell function and immune suppression with assessments directed at CYNK-001 tumor distribution using methodology developed at Celularity Inc. Approximately 66 patients are planned for this Phase I/IIa study. Approximately 66 patients are planned for this Phase I/IIa study. Clinical trial information: NCT05218408.
A combined phase I/II study of a novel bicycle tumor-targeted immune cell agonist BT7480 in patients with nectin-4 associated advanced malignancies.
Authors: Papadopoulos Kyriakos P. , Dowlati Afshin , Dickson Amy , Hirschberg Sandra , Westrup Sally , Upadhyaya Punit , Cohen Heather , Hurov Kristen , Watson Roshawn , Hazard Sebastien , Smethurst Dominic , Rodon Ahnert Jordi
Published: June 2022

TPS2689

Background: BT7480 is a novel, first-in-class, Nectin-4/CD137 Bicycle tumor-targeted immune cell agonist ( Bicycle TICA) that co-ligates cluster of differentiation (CD)137 (on immune cells) and Nectin-4 (on tumor cells). BT7480 comprises 3 bicyclic peptides ( Bicycles), 1 that binds to Nectin-4 and 2 that bind to CD137. The Bicycles are conjugated via a branched trimeric polyethylene glycol linker. Co-ligation of Nectin-4 and CD137 by BT7480 is hypothesized to induce oligomerization and activation of CD137 resulting in a tumor-localized costimulatory signal that leads to an antitumor response in preclinical studies. Nectin-4 is reported to be highly expressed in numerous tumors with unmet medical need including bladder, pancreas, breast, ovary, esophagus, head and neck, stomach, and lung cancers. Many of these tumor types also contain CD137 expressing cells. BT7480 exhibited a favorable preclinical profile supporting initiation of a first-in-human study to investigate safety and efficacy in indications with evidence of Nectin-4 expression. Methods: BT7480-100 (NCT05163041) is a PhI/II study to evaluate safety and tolerability of BT7480 administered as an intravenous infusion QW in a 28-day cycle, and to determine a recommended Phase 2 dose to further explore efficacy and safety. Patients will be recruited with advanced solid tumors associated with Nectin-4 expression including urothelial; head and neck squamous cell; non-small cell lung; ovarian, breast, gastric or esophageal carcinoma after exhausting standard of care options. Patients must have available tumor tissue, acceptable hematologic and other critical organ function. Exclusion criteria include uncontrolled brain metastases, uncontrolled hypertension, significant history of autoimmune disease and prior CD137 targeted therapy. Pharmacokinetic and pharmacodynamic analyses will be performed to support dose escalation decisions and increase the understanding of safety and clinical activity signals observed during the study. Tumor response will be assessed per RECIST every 8 weeks. Cohorts 1 and 2 have been completed without DLT. Enrollment in cohort 3 began in January 2022. Clinical trial information: NCT05163041.
IL believe: A phase 1/2, open-label, dose escalation and dose expansion study of TransCon IL-2 β/γ alone or in combination with pembrolizumab or standard-of-care chemotherapy in patients with locally advanced or metastatic solid tumors.
Authors: Starodub Alexander , Gabrail Nashat Y. , Zhang Ying , Torrejon Castro Davis Y , Slavsky Sibel , Singel Stina Mui , Powderly John D.
Published: June 2022

TPS2695

Background: Advances in immunotherapy have led to significantly improved survival and quality of life in some cancer patients, but many with less immunogenic tumor types derive suboptimal clinical benefit. Recombinant human interleukin-2 (IL-2, aldesleukin) can induce a response rate of ̃15% in metastatic renal cell carcinoma and metastatic melanoma, yet toxicities (vascular leak syndrome, cytokine storm) have limited its use. TransCon IL-2 β/γ, a novel prodrug with sustained release of a receptor-selective IL-2 (IL-2 β/γ), was designed to optimally address drawbacks of aldesleukin: potent activation of undesired IL-2Rα+ cell types and high Cmax with rapid clearance. TransCon IL-2 β/γ comprises 3 main components: IL-2 β/γ, a methoxy polyethylene glycol (mPEG) carrier molecule, and a linker connecting the two. Under physiological conditions, TransCon IL-2 β/γ releases active IL-2 β/γ from the mPEG carrier through cleavage of the TransCon Linker. This results in a lower Cmax and much longer effective t½ of free IL-2 β/γ compared to aldesleukin. PD-1 expression at the cell surface of activated cytotoxic T cells and natural killer cells provides a clear rationale to study TransCon IL-2 β/γ alone or in combination with pembrolizumab. Methods: IL Believe is a multicenter, first-in-human, Phase 1/2 study in 3 parts in adult patients with locally advanced or metastatic solid tumors. All patients need ≥1 measurable lesion per RECIST 1.1 and an ECOG score of ≤ 2. The primary objectives are to evaluate safety and tolerability, and to define the maximum tolerated dose and recommended Phase 2 dose (RP2D) of TransCon IL-2 β/γ alone or in combination with pembrolizumab. Parts 1 and 2 Dose Escalation (Phase 1) use a standard 3+3 design with increasing doses of intravenous (IV) TransCon IL-2 b/g alone (Part 1) or with 200 mg IV pembrolizumab in solid tumors where pembrolizumab monotherapy may have clinical activity (Part 2). Each part will enroll ̃15 patients. Part 3, Combination Dose Expansion (Phase 2) will evaluate preliminary clinical efficacy of TransCon IL-2 β/γ at the RP2D determined in Part 2, combined with chemotherapy. Platinum Resistant Ovarian Cancer is currently planned for dose expansion with other indication specific cohorts to be included in a subsequent amendment. Each cohort will be analyzed using a Simon 2-stage design and will enroll ̃56 patients. Other key objectives include the evaluation of pharmacokinetics, pharmacodynamic biomarkers, and antitumor activity according to RECIST 1.1. Recruitment started in January 2022 and is ongoing (NCT05081609). Clinical trial information: NCT05081609.
An open-label, multicenter, phase 1 study of RP3 as a single agent and in combination with nivolumab in patients (pts) with solid tumors.
Authors: Harrington Kevin Joseph , Rullan Antonio , Deighton Louise , Barata Joao , Castro Henry , Ahlers Christoph Matthias , McRae John , Bommareddy Praveen , Coffin Robert S. , Middleton Mark R.
Published: June 2022

TPS2705

Background: RP3 is a genetically modified herpes simplex virus 1 (HSV-1) that contains insertions for the gibbon ape leukemia virus surface glycoprotein (GALV-GP) with the R- sequence deleted (R-), an anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody-like molecule, CD40 ligand, and 4-1BB ligand. Together, these insertions are expected to increase oncolytic potency, cell-to-cell spread, immunogenic cell death, and systemic immune activation. RP3 has demonstrated antitumor activity in preclinical models using viruses similar to RP3 expressing murine versions of anti-CTLA-4, CD40L, and 4-1BBL both alone and in combination with PD1-1 blockade. Methods: This is an open-label, multicenter, Phase 1 study evaluating RP3 as monotherapy or in combination with nivolumab (nivo) in patients (pts) with solid tumors (NCT04735978). Part 1 evaluated escalating doses of RP3. Pts in Part 1 received IT injections of up to 10 mL RP3 into superficial, nodal, or visceral lesions Q2W x 5 across two dose levels (DL1: 105 plaque-forming units (PFU)/mL once, then 106 PFU/mL x 4; DL2: 106 PFU/mL once, then 107 PFU/mL x4). The RP2D is 106 PFU/mL once, followed by 107 PFU/mL IT Q2W. In Part 2, pts are being enrolled into expansion cohorts of 45 patients with GI (including HCC), lung, breast, and squamous cell carcinoma of the head and neck treated with RP1 combined with nivo. Additional cohorts will enroll patients treated with RP3 followed by nivo, RP3 monotherapy to further explore biomarkers in injected and uninjected tumors, and with the potential to also open a cohort in melanoma. Pts in both Part 1 and Part 2 may receive up to 8 additional doses of RP3 if protocol-specified criteria are met. Key inclusion criteria: confirmed advanced or metastatic non-neurological solid tumors, at least one measurable tumor ≥ 1 cm and injectable tumors ≥ 1 cm in aggregate, ECOG ≤1, and adequate hematologic, hepatic, and renal function. In Cohorts 1, 2, and 4, approximately 50% of the pts with lung, breast, and GI cancer must have liver lesions intended for injection. Exclusion criteria include prior oncolytic virus treatment, need for immunosuppressive therapy, an autoimmune disease requiring systemic therapy, active significant herpetic infections or prior complications of HSV-1 infection, active or chronic HBV or HCV infection, known HIV infection, or prior active malignancy within 3 years. Clinical trial information: NCT04735978.
Phase 1 study of C019199, an oral CSF-1R/DDRs/VEGFR2 multiple kinase inhibitor, to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with advanced solid tumors, including tenosynovial giant cell tumor.
Authors: Shen Lin , Ye Feng , Gong Jifang
Published: June 2022

TPS3177

Background: C019199 was designed to be a tumor immune microenvironment (TME) modulator in order to improve the efficacy against tumor growth when combined with immune checkpoint inhibitors, like anti-PD1 or anti-PD-L1. It was shown to have a specific inhibition profile against CSF-1R, DDR1 and VEGFR2 with IC50 of 14nM, 40nM and 79nM, respectively. CSF-1R’s inhibition may deplete Tumor-associated macrophages (TAMs) in TME, help the infiltration of T cells and enhance T cell responses. But a single modulating mechanism may not be strong enough or may be vulnerable and easily overcome by tumors. C019199 can reshape the TME by additionally inhibiting DDRs and VEGFR2, which may remove the "physical barrier" of tumor extracellular matrix and further increase T cell infiltration on top of inducing tumor blood vessels normalization. As a single agent with the appropriate combination of multiple modulation effects, it will potentially turn "cold" tumors into "hot" tumors. Preclinical studies have shown that C019199 inhibits tumor growth in multiple animal tumor models and has better antitumor efficacy when combined with immune checkpoint blockades. Methods: A first-in-human, open label, multicenter, dose-escalation/expansion study of C019199 is currently enrolling. Eligible subjects (age ≥ 18 years and <76 years) with histologically or cytologically confirmed relapsed, refractory, or progressive metastatic solid tumors will be enrolled in. In Part A, the safety and tolerability of C019199 will be assessed in about 25 subjects to identify the maximum tolerated dose and recommended phase Ⅱ dose (PR2D). In Part B, the safety and antitumor activity of the RP2D will be assessed in about 60 subjects in disease-specific expansion cohorts. Primary endpoints are adverse events, laboratory abnormalities, dose-limiting toxicities. Secondary endpoints will include pharmacokinetics, objective response rate, progression-free survival, and disease control rate. Exploratory biomarker analyses include CSF-1 and VEGF. Clinical trial information: CTR20202045.
Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-US): NRG-GI008.
Authors: Dasari Arvind , Lin Yan , Kopetz Scott , Jacobs Samuel A. , Lucas Peter C. , Sahin Ibrahim Halil , Deming Dustin A. , Philip Philip Agop , Hong Theodore S. , Rojas-Khalil Yesenia , Wolmark Norman , Yothers Greg , George Thomas J. , Lieu Christopher Hanyoung
Published: June 2022

TPS3643

Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage III A, B (all pts) and stage II, IIIC (ctDNA+ only) CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor informed assay (SignateraTM, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP) + oxaliplatin (Ox) for 3-6 mos per established guidelines vs . serial ctDNA monitoring. Patients who are ctDNA+ post-operatively or with serial monitoring (Cohort B) will be randomized to FP+Ox vs . more intensive AC with addition of irinotecan (I) for 6 mos. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) in phase III in the immediate vs . delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox vs FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, post-operative and serial matched/normal blood samples will be collected for exploratory correlative research. Active enrollment across the NCTN started in early 2022. Support: U10-CA-180868, -180822; UG1CA-189867; Clinical trial information: NCT05174169.
Trial in progress: Phase 3 study of bemarituzumab + mFOLFOX6 versus placebo + mFOLFOX6 in previously untreated advanced gastric or gastroesophageal junction (GEJ) cancer with FGFR2b overexpression (FORTITUDE-101).
Authors: Smyth Elizabeth Catherine , Chao Joseph , Muro Kei , Yen Priscilla , Yanes Rolando Eduardo , Zahlten-Kumeli Anita , Rha Sun Young
Published: June 2022

TPS4164

Background: Fibroblast growth factor receptor 2b (FGFR2b) is overexpressed in approximately 30% of non-human epidermal growth factor receptor 2 (non-HER2) positive gastric cancer (Wainberg, 2021). Bemarituzumab is a first-in-class monoclonal antibody that specifically blocks FGFR2b, inhibiting downstream tumor proliferation and enhancing antibody-dependent cellular cytotoxicity (Catenacci, 2020; Xiang, 2021). In the phase 2 FIGHT study (Wainberg, 2021; Catenacci, 2021), bemarituzumab + mFOLFOX6 improved progression-free survival (PFS; HR, 0.68; 95% CI, 0.44‒1.04; p = 0.07) and led to a 5.7 month longer median overall survival (OS; 19.2 months vs 13.5 months; HR, 0.60; 95% CI, 0.38-0.94) compared with placebo + mFOLFOX6. Methods: FORTITUDE-101 (NCT05052801) is a double-blind, placebo-controlled phase 3 study in patients with untreated, unresectable locally advanced or metastatic gastric or GEJ adenocarcinoma not amenable to curative therapy. Approximately 516 patients aged ≥18 years with IHC-confirmed FGFR2b overexpression by central testing will be enrolled and randomized 1:1 to bemarituzumab + mFOLFOX6 or placebo + mFOLFOX6. Additional key eligibility criteria include Eastern Cooperative Oncology Group performance status 0-1, evaluable disease per RECIST v1.1, adequate hematologic and organ function, and no contraindication to receive mFOLFOX6 chemotherapy. Key exclusion criteria include prior treatment for metastatic or unresectable disease except one dose of mFOLFOX6 during screening, positive HER2 status, untreated or symptomatic CNS metastasis and leptomeningeal disease, history or evidence of ongoing ophthalmologic abnormalities, and prior treatment with any FGF-FGFR pathway inhibitor. Patients randomized to bemarituzumab will receive 15 mg/kg every 2 weeks (Q2W) with an additional 7.5 mg/kg dose on cycle 1 day 8. mFOLFOX6 will be administered at a fixed dose Q2W. Patients will receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint is OS; secondary endpoints include PFS, objective response (defined as best overall response of complete or partial response), and treatment-emergent adverse events. Tumor responses and PFS will be assessed locally per RECIST v1.1. The concurrent phase 1b/3 FORTITUDE-102 study (NCT05111626) will evaluate the efficacy and safety of bemarituzumab + mFOLFOX6 + nivolumab versus placebo + mFOLFOX6 + nivolumab. Clinical trial information: NCT05052801.
An investigator-initiated phase II trial of a PARP inhibitor niraparib monotherapy for patients with pre-treated, BRCA-mutated, unresectable/recurrent biliary tract, pancreatic, and other gastrointestinal cancers (NIR-B trial).
Authors: Kawamoto Yasuyuki , Morizane Chigusa , Komatsu Yoshito , Ueno Makoto , Ikeda Masafumi , Furukawa Masayuki , Satoh Taroh , Hatanaka Yutaka , Yokota Isao , Nakamura Yoshiaki , Yoshino Takayuki ,   SCRUM-Japan MONSTAR-SCREEN
Published: June 2022

TPS4174

Background: Recent comprehensive genomic profiling tests have revealed therapeutic target molecules. However, because many targets are present in only a small fraction of patients, a large number of patients need to be screened for enrollment in a single study. In order to overcome this patient identification barrier, the SCRUM-Japan, nationwide large-scale genomic profiling platform, efficiently has been performed umbrella- and basket-type clinical trials. Among the platforms, we have reported that there are BRCA1/2-mutated patients in biliary tract, pancreatic, and other gastrointestinal cancers. Niraparib is an anticancer drug belonging to poly(ADP-ribose) polymerase (PARP) inhibitors. Niraparib has been shown to be selective for PARP1/2, to be more cytotoxic among other PARP inhibitor because of its PARP trapping activity. Methods: This is an investigator-initiated, multicenter, three-cohort phase 2 study. Main eligibility criteria are unresectable, advanced or recurrent biliary tract cancers (cohort A), pancreatic cancers (cohort B), and other gastrointestinal cancers (cohort C) with BRCA1/2 gene mutations identified by germline test or genomic profiling test with either circulating tumor DNA (ctDNA) or tumor tissue, refractory or intolerant to previous treatments, and adequate organ function. Primary endpoint is the investigator-assessed objective response rate in each cohort with a threshold-response rate of 10% and an expected response rate of 35%. Key secondary endpoints are progression-free survival, overall survival, disease control rate, duration of response, and safety. Patients with body weight of 77 kg or more and a platelet count of 150,000 /µL or more receive 300 mg of niraparib, and less than 77 kg or having a platelet count less than 150,000 /µL receive 200 mg of niraparib, orally once daily. Furthermore, pre-treatment tumor tissue and serial ctDNA will be collected and analyzed to investigate the resistance mechanisms and provide clinically meaningful biomarker which may be used for identifying and implementing treatment changes. The trial was initiated in January 2021 with enrollment being ongoing. Thirty-three out of planned 60 patients (cohort A/B/C; 25/25/10, respectively) have been enrolled as of December 2021. Funding: Takeda Pharmaceutical Co., Ltd. Clinical trial information: jRCT2011200023.
An open-label, multicenter, randomized phase II study of atezolizumab and bevacizumab with Y90 TARE in patients with unresectable hepatocellular carcinoma (HCC).
Authors: He Aiwu Ruth , Banovac Filip , Iyer Renuka V. , Petroziello Michael , Brown Daniel , Goff Laura Williams , Kim Richard D. , Parikh Nainesh , Toskich Beau , Kim Kevin , Jiang Yixing , Ganguli Suvranu , Kulke Matthew H. , Armstrong Samantha Ann , Johnson Matthew , Shroff Rachna T. , Woodhead Gregory
Published: June 2022

TPS4177

Background: The anti–PD-L1 antibody atezolizumab (ATEZO) prevents PD-L1 from interacting with PD-1 and B7.1, thus reinvigorating antitumor T cell activity. Anti-VEGF bevacizumab (BEV) increases dendritic cell maturation, enhances T cell infiltration, and reduces myeloid-derived suppressor cells and regulatory T cells in tumors. ATEZO + BEV is FDA approved for first-line treatment of advanced HCC based on the IMbrave 150 study. Locoregional radiotherapy (e.g., Y90 TARE) enhances the diversity of the intratumoral T cell receptor repertoire and increases tumor antigen release. We hypothesize that the Y90 TARE + BEV + ATEZO combination induces synergistic tumor killing and prolongs progression-free survival in patients (pts) receiving Y90 TARE (HR = 0.6 when compared to Y-90 TARE alone). Methods: Eligible pts have HCC that cannot be surgically resected (confirmed by pathology review), is at least BCLC stage B, and is outside Milan criteria. Other requirements include ECOG PS of 0-1 at screening, measurable disease by RECIST 1.1, no prior systemic therapy, and FLR estimated at ≥ 40% post local therapy. Pts must have a pretreatment liver biopsy taken and then be randomized 1:1 to TARE (Arm A) or TARE + ATEZO + BEV (Arm B). Pts will have TARE mapping followed by TARE treatment. In Arm B, pts will begin TARE treatment followed by BEV + ATEZO (4 wks [± 1 wk] later). Pts will have abdominal MRI or CT scans every 12 weeks and CT scans of the chest every 24 wks. The primary study objective is to assess and compare pts' progression-free survival (per mRECIST 1.1) in each study arm. The main secondary objective is to determine the safety and tolerability (CTCAE v5) of pts in Arm B. Exploratory objectives are to define the use of cellular and circulating biomarkers in the prediction of improved clinical outcomes of pts in Arm B. Symptoms experienced by pts in both arms using patient-reported outcomes will be assessed. Disease progression will be captured by both RECIST 1.1 and mRECIST. We plan to assess the safety of Y90 TARE + BEV + ATEZO in the first 10 pts randomized to Arm B for two cycles, and if there are no grade ≥ 3 unexpected toxicities possibly, probably, or definitely related to combined TARE + BEV + ATEZO, continue to accrue 128 pts in total (current enrollment n- = 5). Pts will continue study treatment (Arm B) for a total of 24 months from initiation of TARE or until intolerable toxicity or disease progression occur, whichever is earlier. Enrollment began in September 2020. Clinical trial information: NCT04541173.
A multicenter, randomized, double-blind phase III clinical study to evaluate the efficacy and safety of KN046 combined with nab-paclitaxel and gemcitabine versus placebo combined with nab-paclitaxel and gemcitabine in patients with advanced pancreatic cancer (ENREACH-PDAC-01).
Authors: Jin Gang , Guo Shiwei , Xu Jianming , Liu Rongrui , Liang Qianqian , Yang Yong , Guo Baohong , Xu Yiqi , Xia Binyan , Zhang Chao , Zhu Shengxia , Xu Ting
Published: June 2022

TPS4189

Background: Pancreatic cancer is biologically aggressive, and the majority of pts was diagnosed as locally advanced or metastatic disease. Nab-paclitaxel and gemcitabine is a frequently used regimen for advanced pancreatic cancer, but chemoresistance is unavoidable. The combination of immunotherapy with chemotherapy have shown efficacy for certain types of cancer, but no similar results have been obtained in pancreatic cancer. KN046, a novel recombinant humanized bispecific antibody, can simultaneously block PD-1/PD-L1 and CTLA-4 pathways and restore T-cell immune response to tumor. In a phase Ⅱ clinical trial (NCT04324307), as of August 10, 2021, 53 pts with unresectable advanced pancreatic cancer had received one cycle KN046 combined AG regimen treatment and 31 subjects had received post-baseline tumor assessment at least once. Objective response rate (ORR) was 45.2% (95% CI: 27.3%, 64.0%) and disease control rate (DCR) was 93.5% (95% CI: 78.6%, 99.2%)，excellent preliminary results have been achieved. Based on this, a phase III pivotal study (ENREACH-PDAC-01) is conducting now in China to verify the efficacy and safety of KN046 plus nab-paclitaxel and gemcitabine as first-line treatment for advanced pancreatic cancer (NCT05149326). Methods: This nationwide multicenter phase III clinical trial enrolled pts with histologically or cytologically confirmed unresectable locally advanced or metastatic pancreatic ductal adenocarcinomas with a WHO performance score of 0 or 1 and expected survival period of more than 3 months. Eligible pts will be randomized 1:1 to intervention group or control group and receive 4-6 cycles of KN046 (5mpk Q2W) or placebo combined with nab-paclitaxel (initial dose: 125mg/m2 D1,8,15 Q4W) and gemcitabine (initial dose: 1000mg/m2 D1,8,15 Q4W) followed by KN046 (5mpk Q2W) or placebo with gemcitabine（QW × 3, 1 week off） maintenance therapy. Treatment will continue until disease progression or intolerable toxicity, withdrawal of consent, loss to follow-up or death, end of study, whichever occurs first. The primary endpoint is overall survival (OS). Key secondary endpoints are ORR and progression free survival (PFS). PFS and ORR will be assessed independently per RECIST v1.1 at screening, every 8 weeks for 1 year and then every 12 weeks until disease progression. Tumor and blood samples will be collected at baseline and during study treatment for pharmacokinetic, immunogenicity and biomarker assessment. The first patient was enrolled in early February 2022. Clinical trial information: NCT05149326.