A phase I/IIa, open label, clinical trial evaluating the safety and efficacy of autologous T cells expressing enhanced TCRs specific for NY-ESO-1 in patients with recurrent or treatment refractory ovarian cancer (NCT01567891).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3094-TPS3094
Author(s):  
Kunle Odunsi ◽  
Mihaela C. Cristea ◽  
Oliver Dorigo ◽  
Amir A. Jazaeri ◽  
Brian M. Slomovitz ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
Lentiviral Vector ◽  
Gynecologic Cancer ◽  
Progression Free Survival ◽  
Survival Duration ◽  
Open Label ◽  
Resistant Disease ◽  
Duration Of Response

TPS3094 Background: Epithelial ovarian cancer comprises the majority of malignant ovarian neoplasms (~80%) and is the leading cause of death from gynecologic cancer in the US. Due to lack of effective screening strategies, the majority (63%) of patients are diagnosed with ovarian cancer at advanced stages. New therapies are needed to address the unmet medical need of patients with ovarian cancer. 11-40% of ovarian cancers express NY-ESO-1 cancer testis/antigen. This study is evaluating affinity enhanced autologous NY-ESO-1c259T cells recognizing an NY-ESO-1 derived peptide complexed with HLA-A*02 in ovarian cancer. Methods: This single arm, open label clinical trial is evaluating safety and tolerability, antitumor activity (response rate by RECIST v1.1, progression free survival, overall survival, duration of response), and translational research endpoints. The study evaluates two lymphodepleting regimens: cyclophosphamide (enrolment completed; n = 7) and cyclophosphamide plus fludarabine (at least 10 subjects to be enrolled). Subjects must be ≥ 18 years old; HLA-A*02:01, *02:05, or *02:06 positive; have recurrent epithelial ovarian, primary peritoneal or fallopian tube carcinoma with refractory or platinum-resistant disease expressing NY-ESO-1 by IHC; have measurable disease; have ECOG status 0 or 1; and have adequate organ function. Following apheresis, the T cells are isolated and expanded with CD3/CD28 beads, transduced with a lentiviral vector containing the NY-ESO-1c259 TCR, and 1 – 6 × 109 transduced T cells are infused intravenously on Day 0 after lymphodepletion with fludarabine 30 mg/m2/day and cyclophosphamide 600 mg/m2/day on days -7 to -5. Response is assessed at weeks 4, 8, 12 and 24, and then every 3 months until confirmation of disease progression. Clinical trial information: NCT01567891.

A pilot study of NY-ESO-1c259 T cells in subjects with advanced myxoid/round cell liposarcoma (NCT02992743).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3097-TPS3097 ◽  
Author(s):  
Sandra P. D'Angelo ◽  
Mihaela Druta ◽  
George D. Demetri ◽  
David A. Liebner ◽  
Scott Schuetze ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Pilot Study ◽  
Lentiviral Vector ◽  
Soft Tissue Sarcomas ◽  
Progression Free Survival ◽  
Response Duration ◽  
Genetically Engineered ◽  
Round Cell ◽  
Open Label

TPS3097 Background: Myxoid/round cell liposarcomas (MRCLS) account for 6-10% of soft tissue sarcomas. Although a chemosensitive tumor, metastatic MRCLS has a poor prognosis and is inevitably fatal. More effective, durable and less toxic therapies are needed. NY-ESO-1 is a cancer/testis antigen that is expressed in 80-90% of MRCLS tumors. This study will evaluate the safety and efficacy of genetically engineered affinity enhanced autologous NY-ESO-1c259T cells recognizing an NY-ESO-1 derived peptide complexed with HLA-A*02 in MRCLS. Methods: This open label phase I/II non-randomized pilot study will evaluate efficacy (overall response rate by RECIST v1.1, time to response, duration of response, progression free survival, overall survival), safety, and translational research endpoints. Patients must meet these criteria: ≥ 18 yrs old; HLA-A*02:01, *02:05 or *02:06 positive; have advanced (metastatic or inoperable) MRCLS expressing NY-ESO-1 at 2+/3+ intensity in ≥30% of tumor cells by IHC; measurable disease; prior systemic anthracycline therapy; have ECOG status 0 or 1; and adequate organ function. Initially, ten patients are planned to be enrolled, with potential to enroll an additional 5 patients. Patients who do not receive the minimum cell dose or who do not receive the T-cell infusion may be replaced. Following apheresis, the T cells are isolated and expanded with CD3/CD28 beads, transduced with a lentiviral vector containing the NY-ESO-1c259 TCR, and 1– 8 × 109 transduced T-cells are infused intravenously on Day 1 after lymphodepletion with fludarabine 30 mg/m2/day and cyclophosphamide 600 mg/m2/day on days -7 to -5. Response is assessed at 4, 8, 12 and 24 weeks, and then every 3 months until confirmation of progression of disease. On study tumor biopsies and blood samples will be evaluated to compare the pre- and post-T cell infusion immune profile for association with treatment outcome. Clinical trial information: NCT02992743.

Anlotinib in combination with TQB2450 in patients with recurrent ovarian cancer (ACTION): A multicenter, single-arm, open-label, phase Ib trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5557-5557
Author(s):  
Chunyan Lan ◽  
Jing Zhao ◽  
Fan Yang ◽  
Rong Li ◽  
Yu Huang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Group Performance ◽  
Gynecologic Cancer ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Advanced Ovarian Cancer ◽  
Open Label ◽  
Phase Ib ◽  
Platinum Based Chemotherapy ◽  
Duration Of Response

5557 Background: Combination of antiangiogenic therapy and immune checkpoint inhibitor therapy is reported as an effective antitumor strategy. TQB2450 is a humanized IgG1 monoclonal antibody against programmed death-ligand 1 (PD-L1). We aimed to assess the activity and safety of TQB2450 plus the antiangiogenic multi-target tyrosine kinase inhibitor anlotinib in patients with recurrent advanced ovarian cancer. Methods: The study with ClinicalTrials.gov identifier NCT04236362 is an open-label, multicohort, and multicenter phase Ib trial evaluating the efficacy and safety of anlotinib combined with TQB2450 in patients with advanced gynecologic cancer. The present study (ACTION study) reports the ovarian cancer cohort. We enrolled patients aged 18–70 years with platinum-resistant or platinum-refractory epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST). Eligible patients received anlotinib 12 mg per day orally on days 1 to 14 and TQB2450 1200 mg intravenously on day 1, every three weeks. Treatment continued until disease progression, unacceptable toxicity, and withdrawal of consent. The primary endpoint was objective response rate (ORR) assessed by investigators according to RECIST version 1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety. Results: Between 21 Feb 2020 and 15 Jan 2021, 33 patients with a median age of 55 years (range, 26-71) were enrolled and received study treatment. Patients had received at least once platinum-based chemotherapy, and the median number of previous chemotherapy lines was 3 (range, 1–6). 30.3% patients had bevacizumab therapy before enrollment. At data cutoff (15 Jan 2021), the median follow-up was 5.1 months (range, 0.1–10.8). In the 25 efficacy-evaluable patients, 13 of them achieved partial response, yielding the ORR of 52.0% (95% CI, 30.4%–71.6%). The median PFS was 6.7 months (95% CI, 4.5 months to not reached). The median duration of response and the median OS were not reached. The treatment-related grade 3 or 4 adverse events (AEs) occurred in 54.5% patients, and the most common ones were palmar-plantar erythrodysesthesia syndrome (21.2%) and hypertension (18.2%). The most potential immune-related AEs included grade 1 to 2 hypothyroidism (24.2%) and fatigue (9.1%). No treatment-related death was recorded. Conclusions: Anlotinib plus TQB2450 showed encouraging antitumor activity and tolerable toxicity in patients with recurrent advanced ovarian cancer. Clinical trial information: NCT04236362.

scholarly journals FIGHT-302: first-line pemigatinib vs gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements

2020 ◽  
Vol 16 (30) ◽  
pp. 2385-2399 ◽  
Author(s):  
Tanios S Bekaii-Saab ◽  
Juan W Valle ◽  
Eric Van Cutsem ◽  
Lorenza Rimassa ◽  
Junji Furuse ◽  
...  
Keyword(s):  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Survival Duration ◽  
Efficacy And Safety ◽  
First Line ◽  
Open Label ◽  
Clinical Trial Registration ◽  
Duration Of Response

FGFR2 rearrangements resulting in dysregulated signaling are drivers of cholangiocarcinoma (CCA) tumorigenesis, and occur almost exclusively in intrahepatic CCA. Pemigatinib, a selective, potent, oral inhibitor of FGFR1–3, has demonstrated efficacy and safety in a Phase II study of patients with previously treated locally advanced/metastatic CCA harboring FGFR2 fusions/rearrangements. We describe the study design of FIGHT-302, an open-label, randomized, active-controlled, multicenter, global, Phase III study comparing the efficacy and safety of first-line pemigatinib versus gemcitabine plus cisplatin in patients with advanced CCA with FGFR2 rearrangements (NCT03656536). The primary end point is progression-free survival; secondary end points are objective response rate, overall survival, duration of response, disease control rate, safety and quality of life. Clinical Trial Registration: NCT03656536 ( ClinicalTrials.gov )

A phase I single arm, open label clinical trial evaluating safety of MAGE-A10c796T in subjects with advanced or metastatic head and neck, melanoma, or urothelial tumors (NCT02989064).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3098-TPS3098 ◽  
Author(s):  
David S. Hong ◽  
Marcus O. Butler ◽  
Ryan J. Sullivan ◽  
Connie L. Erickson-Miller ◽  
Trupti Trivedi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Head And Neck ◽  
Lentiviral Vector ◽  
Head And Neck Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Neck Tumors ◽  
Human T Cell

TPS3098 Background: MAGE-A10 is a cancer/testis antigen that has been identified in 42, 26 and 17% of urothelial, melanoma and head and neck tumors, respectively. This study will evaluate the safety and antitumor activity of genetically engineered affinity enhanced autologous MAGE-A10c796T cells directed towards a MAGE-A10 peptide expressed on tumors in the context of HLA *02:01 and/or *02:06. Methods: This first-in-human T cell dose escalation study utilizes a modified 3+3 design to evaluate safety, including dose limiting toxicities (DLT). Secondary objectives include anti-tumor activity (overall response, duration of response, time to response, PFS, OS) and translational research assessments. Patients are screened under a separate protocol (NCT02636855). Those who are HLA*02:01 and/or *02:06 positive and have inoperable or metastatic (advanced) urothelial cancer, melanoma, or squamous cell head and neck tumors with MAGE-A10 expression and meet all other entry criteria are eligible for treatment. Patients must have received standard of care therapies and have progressive disease. Following apheresis, the T cells are isolated and expanded with CD3/CD28 beads, transduced with a lentiviral vector containing the MAGE-A10c796 TCR, and infused into the subject (Day 1) after receiving lymphodepleting chemotherapy (fludarabine 30 mg/m2/day and cyclophosphamide 600 mg/m2/day, on days -7, -6 and -5). The DLT observation period will be during the first 30 days following the infusion of MAGE-A10c796T for each patient in all groups. Up to 10 patients will be enrolled at the target dose. Disease assessments will be conducted at week 6, 12, 18 and 24, and then every 3 months until confirmation of disease progression. On study tumor biopsies and blood samples will be evaluated to compare the pre- and post-T cell infusion immune profile for association with treatment outcome. Clinical trial information: NCT02989064. [Table: see text]

Cediranib in combination with olaparib in patients without a germline BRCA1/2 mutation with recurrent platinum-resistant ovarian cancer: Phase IIb CONCERTO trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6056-6056
Author(s):  
Jung-min Lee ◽  
Richard G. Moore ◽  
Sharad A. Ghamande ◽  
Min S. Park ◽  
John Paul Diaz ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trial ◽  
Response Rate ◽  
Brca Mutation ◽  
Objective Response ◽  
Progression Free Survival ◽  
Open Label ◽  
Repair Gene ◽  
Platinum Resistant ◽  
Platinum Based Chemotherapy

6056 Background: A Phase I trial (NCT01116648) of cediranib (cedi) in combination with olaparib (ola) (cedi + ola) demonstrated an overall response rate of 44% in patients (pts) with recurrent ovarian cancer (OC), including pts without a deleterious or suspected deleterious gBRCAm (non-gBRCAm; Liu et al. Eur J Cancer 2013). The subsequent Phase II trial (NCT01116648) showed significant improvement in progression-free survival (PFS) with cedi + ola versus ola monotherapy in recurrent platinum-sensitive OC pts, notably in non-gBRCAm pts (Liu et al. Lancet Oncol 2014). We report data from the Phase IIb, single-arm, open-label CONCERTO study investigating cedi + ola in non-gBRCAm pts with recurrent platinum-resistant OC who had received ≥3 previous lines of therapy for advanced OC (NCT02889900). Methods: Pts with disease progression <6 months from the last receipt of platinum-based chemotherapy received cedi tablets (30 mg once daily) plus ola tablets (200 mg twice daily) until progression or unacceptable toxicity. gBRCAm pts were ineligible. Primary endpoint: objective response rate (ORR) by independent central review (ICR; RECIST 1.1). Key secondary endpoints: PFS and safety. Results: 60 pts from the USA were included (median age: 64.5 years; median number of previous systemic treatment regimens: 4 [range: 2–9]; previous bevacizumab: 53). All pts had high-grade OC (90% serous; 3.3% clear cell; 3.3% endometrioid; 3.3% other). 7% of pts had tumor BRCA2 (confirmed somatic) mutations, 80% of pts had no tumor BRCA mutation (non-tBRCAm) and 13% of pts were not evaluable for tBRCAm. Five (8%) pts who were non-tBRCAm carried somatic homologous recombination repair gene mutations (FoundationOne Clinical Trial Assay, Foundation Medicine, Inc). The Table shows results of key endpoints. Most common grade ≥3 adverse events (AEs) that occurred in pts were hypertension (30%), fatigue (22%) and diarrhea (13%). 37% of pts reported serious AEs, of which nausea (7%) was most common. Dose interruptions, reductions and discontinuations were caused by AEs in 55%, 18% and 18% of pts, respectively, who received cedi + ola. Conclusions: Cedi + ola showed evidence of antitumor activity in heavily pretreated non-gBRCAm pts with recurrent platinum-resistant OC. Toxicity was manageable with dose modifications. Clinical trial information: NCT02889900. [Table: see text]

scholarly journals Differential expression of SLIT and NTRK-like family member 3 in human epithelial ovarian cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Family Member ◽  
Fallopian Tube ◽  
Expression Profiles ◽  
Gynecologic Cancer ◽  
Progression Free Survival ◽  
High Grade ◽  
Primary Tumors ◽  
Ovarian Cancers

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer (1). We performed discovery of genes associated with epithelial ovarian cancer and of the high-grade serous ovarian cancer (HGSC) subtype, using published and public microarray data (2, 3) to compare global gene expression profiles of normal ovary or fallopian tube with that of primary tumors from women diagnosed with epithelial ovarian cancer or HGSC. We identified the gene encoding SLIT and NTRK-like family member 3, SLITRK3, as among the genes whose expression was most different in epithelial ovarian cancer as compared to the normal fallopian tube. SLITRK3 expression was significantly lower in high-grade serous ovarian tumors relative to normal fallopian tube. SLITRK3 expression correlated with progression-free survival in patients with ovarian cancer. These data indicate that expression of SLITRK3 is perturbed in epithelial ovarian cancers broadly and in ovarian cancers of the HGSC subtype. SLITRK3 may be relevant to pathways underlying ovarian cancer initiation (transformation) or progression.

scholarly journals Differential expression of sarcospan in human epithelial ovarian cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Fallopian Tube ◽  
Expression Profiles ◽  
Gynecologic Cancer ◽  
Gene Expression Profiles ◽  
Progression Free Survival ◽  
High Grade ◽  
Primary Tumors ◽  
Ovarian Cancers

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer (1). We performed discovery of genes associated with epithelial ovarian cancer and of the high-grade serous ovarian cancer (HGSC) subtype, using published microarray data (2, 3) to compare global gene expression profiles of normal ovary or fallopian tube with that of primary tumors from women diagnosed with epithelial ovarian cancer or HGSC. We identified the gene encoding sarcospan, SSPN, as among the genes whose expression was most different in epithelial ovarian cancer as compared to the normal fallopian tube. SSPN expression was significantly lower in high-grade serous ovarian tumors relative to normal fallopian tube. SSPN expression correlated with progression-free survival in patients with ovarian cancer. These data indicate that expression of SSPN is perturbed in epithelial ovarian cancers broadly and in ovarian cancers of the HGSC subtype. SSPN may be relevant to pathways underlying ovarian cancer initiation (transformation) or progression.

scholarly journals Differential expression of phosphodiesterase 5A in human epithelial ovarian cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Fallopian Tube ◽  
Expression Profiles ◽  
Gynecologic Cancer ◽  
Gene Expression Profiles ◽  
Progression Free Survival ◽  
High Grade ◽  
Primary Tumors ◽  
Ovarian Cancers

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer (1). We performed discovery of genes associated with epithelial ovarian cancer and of the high-grade serous ovarian cancer (HGSC) subtype, using published microarray data (2, 3) to compare global gene expression profiles of normal ovary or fallopian tube with that of primary tumors from women diagnosed with epithelial ovarian cancer or HGSC. We identified the gene encoding phosphodiesterase 5A, PDE5A, as among the genes whose expression was most different in epithelial ovarian cancer as compared to the normal fallopian tube. PDE5A expression was significantly lower in high-grade serous ovarian tumors relative to normal fallopian tube. PDE5A expression correlated with progression-free survival in patients with p53 mutant ovarian cancer. These data indicate that expression of PDE5A is perturbed in epithelial ovarian cancers broadly and in ovarian cancers of the HGSC subtype. PDE5A may be relevant to pathways underlying ovarian cancer initiation (transformation) or progression.

scholarly journals Dabrafenib and Trametinib in Patients With Tumors With BRAFV600E Mutations: Results of the NCI-MATCH Trial Subprotocol H

2020 ◽  
Vol 38 (33) ◽  
pp. 3895-3904 ◽  
Author(s):  
April K. S. Salama ◽  
Shuli Li ◽  
Erin R. Macrae ◽  
Jong-In Park ◽  
Edith P. Mitchell ◽  
...  
Keyword(s):  
Overall Survival ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Open Label ◽  
Match Trial ◽  
Efficacy Analysis ◽  
End Point ◽  
Duration Of Response ◽  
Tumor Types

PURPOSE BRAFV600 mutations are commonly found in melanoma and thyroid cancers and to a lesser degree in other tumor types. Subprotocol H (EAY131-H) of the NCI-MATCH platform trial sought to investigate the selective BRAF inhibitor dabrafenib and the MEK1/2 inhibitor trametinib in patients with solid tumors, lymphomas, or multiple myeloma whose tumors harbored a BRAFV600 mutation. PATIENTS AND METHODS EAY131-H is an open-label, single-arm study. Patients with melanoma, thyroid, or colorectal cancer were excluded; patients with non–small-cell lung cancer were later excluded in an amendment. Patients received dabrafenib 150 mg twice per day and trametinib 2 mg per day continuously until disease progression or intolerable toxicity. The primary end point was centrally assessed objective response rate (ORR); secondary end points included progression-free survival (PFS), 6-month PFS, and overall survival. RESULTS Thirty-five patients were enrolled, and 29 were included in the primary efficacy analysis as prespecified in the protocol. Median age was 59 years, and 45% of the patients had received ≥ 3 lines of therapy. The confirmed ORR was 38% (90% CI, 22.9% to 54.9%) with P < .0001 against a null rate of 5%, and PFS was 11.4 months (90% CI, 8.4 to 16.3 months); responses were seen in 7 distinct tumor types. Seven patients had a duration of response of > 12 months, including 4 patients with a duration of response of > 24 months. An additional 8 patients had a PFS > 6 months. The median overall survival was 28.6 months. Reported adverse events were comparable to those noted in previously reported profiles of dabrafenib and trametinib. CONCLUSION This study met its primary end point, with an ORR of 38% ( P < .0001) in this mixed histology, pretreated cohort. This promising activity warrants additional investigations in BRAFV600-mutated tumors outside of currently approved indications.

scholarly journals Single-agent belantamab mafodotin for relapsed/refractory multiple myeloma: analysis of the lyophilised presentation cohort from the pivotal DREAMM-2 study

2020 ◽  
Vol 10 (10) ◽  
Author(s):  
Paul G. Richardson ◽  
Hans C. Lee ◽  
Al-Ola Abdallah ◽  
Adam D. Cohen ◽  
Prashant Kapoor ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Agent ◽  
Pathological Finding ◽  
Progression Free Survival ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Blurred Vision ◽  
Refractory Multiple Myeloma ◽  
Open Label Phase ◽  
Duration Of Response

Abstract DREAMM-2 (NCT03525678) is an ongoing global, open-label, phase 2 study of single-agent belantamab mafodotin (belamaf; GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, in a frozen-liquid presentation in patients with relapsed/refractory multiple myeloma (RRMM). Alongside the main study, following identical inclusion/exclusion criteria, a separate patient cohort was enrolled to receive belamaf in a lyophilised presentation (3.4 mg/kg, every 3 weeks) until disease progression/unacceptable toxicity. Primary outcome was independent review committee-assessed overall response rate (ORR). Twenty-five patients were enrolled; 24 received ≥1 dose of belamaf. As of 31 January 2020, ORR was 52% (95% CI: 31.3–72.2); 24% of patients achieved very good partial response. Median duration of response was 9.0 months (2.8–not reached [NR]); median progression-free survival was 5.7 months (2.2–9.7); median overall survival was not reached (8.7 months–NR). Most common grade 3/4 adverse events were keratopathy (microcyst-like corneal epithelial changes, a pathological finding seen on eye examination [75%]), thrombocytopenia (21%), anaemia (17%), hypercalcaemia and hypophosphatemia (both 13%), neutropenia and blurred vision (both 8%). Pharmacokinetics supported comparability of frozen-liquid and lyophilised presentations. Single-agent belamaf in a lyophilised presentation (intended for future use) showed a deep and durable clinical response and acceptable safety profile in patients with heavily pre-treated RRMM.

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