Preliminary evidence of activity of pralatrexate in relapsed/refractory ovarian cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15557-e15557
Author(s):  
Nashat Y. Gabrail ◽  
Carrie L. Smith
Keyword(s):  
Ovarian Cancer ◽  
Renal Impairment ◽  
Renal Insufficiency ◽  
Solid Tumors ◽  
Hematological Malignancies ◽  
Folate Receptor ◽  
Ca 125 ◽  
Clinical Activity ◽  
Weekly Dose ◽  
The Impact

e15557 Background: Pralatrexate, a novel antifolate, is approved in the US for the treatment of relapsed/refractory peripheral T-cell lymphoma at a dose of 30mg/m2 weekly for 6 weeks of a 7-week cycle. Previous studies in solid tumors have focused on a q2w schedule at 190mg/m2. As pralatrexate is 30-40% renally excreted, an ongoing renal impairment study is investigating the impact of mild, moderate and severe renal impairment on pralatrexate distribution in patients with hematological malignancies and solid tumors. As folate receptor alpha is frequently overexpressed in epithelial ovarian cancers, we hypothesized that ovarian cancer may be a target for pralatrexate treatment and therefore have included a number of ovarian cancer patients in this trial. Methods: Patients with solid tumors and hematological malignancies were enrolled in a phase I clinical trial. Patients are treated in cohorts depending on renal function normal, mild renal insufficiency, moderate renal insufficiency and severe non-dialysis dependent renal failure. This analysis is limited to 6 patients with refractory ovarian cancer. The dose of pralatrexate is 30mg/m2 weekly for 6 weeks of a 7-week cycle, with dose adjustment depending on toxicity. Results: The 6 patients, all with stage 4 refractory ovarian cancer had received 4 or more prior chemotherapy regimens and had refractory disease, defined as, nonresponsive to the last chemotherapy regimen or progression within 3 months of the last dose of chemotherapy. Of the 6 patients, 2 experienced objective responses lasting 9 months and 4 months respectively. Disease response was assessed by CA- 125 and RECIST criteria. Two patients experienced stable disease for 4 months and 5 months respectively. One patient had grade 5 mucositis after the second weekly dose and one patient had progressive disease after disease stabilization for 3 months. Conclusions: Pralatrexate given at a dose of 30mg/m2 to patients with refractory ovarian cancer has demonstrable activity that needs to be confirmed in well-designed efficacy trials. Importantly, this is the first demonstration of clinical activity in a solid tumor at the currently approved dose.

Selinexor in combination with weekly paclitaxel in patients with advanced or metastatic solid tumors: Results of an open label, single-center, multiarm phase 1b study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5565-5565
Author(s):  
Shannon Neville Westin ◽  
Siqing Fu ◽  
Apostolia Maria Tsimberidou ◽  
Sarina Anne Anne Piha-Paul ◽  
Fechukwu Akhmedzhanov ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Solid Tumors ◽  
Clinical Benefit ◽  
Nuclear Export ◽  
Nuclear Accumulation ◽  
Weekly Paclitaxel ◽  
Clinical Activity ◽  
Single Center ◽  
Open Label ◽  
Phase 1B

5565 Background: Selinexor is a first-in-class novel, oral potent selective inhibitor of nuclear export (SINE) which blocks Exportin-1 (XPO1) leading to nuclear accumulation and activation of tumor suppressor proteins and prevention of translation of proto-oncogenes. Weekly paclitaxel is a standard chemotherapy regimen used in various tumor types. Preclinical models show that selinexor with paclitaxel exerts antitumor activity against multiple solid tumors. Our objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of selinexor and weekly paclitaxel. Methods: This was an open label, single-center, multi-arm phase 1b study utilizing a “3 + 3” design and a “basket type” expansion. Selinexor (twice weekly orally) and weekly paclitaxel (80mg IV 2 week on, 1 week off) was employed as one of 13 parallel arms. Two dose levels (DL) of selinexor were explored: DL1 selinexor 60mg; DL2 selinexor 80mg. Patients (pts) with advanced or metastatic solid tumors were eligible if they had adequate bone marrow and organ function. There was no limit on prior lines of therapy. Efficacy was evaluated using RECIST 1.1. Progression free survival (PFS) was defined as time from treatment until disease progression or death. Results: Of 35 pts treated, all were evaluable for toxicity, and 31 (88%) were evaluable for response. Pt diagnoses included ovarian (n = 28), breast (n = 4), prostate (n = 2), and cervical (n = 1) cancer. Pts had a median of four prior therapies (range 1-10), and 47% had a prior taxane. All pts with ovarian cancer had platinum resistant/refractory disease; high grade serous histology was most common. There were no DLTs and DL1 was chosen as the RP2D given its long term tolerability. 97% of pts had at least one treatment-emergent adverse event (TEAE) and the most common TEAEs were anemia (74%), nausea (57%), fatigue (51%), leukopenia (51%), neutropenia (49%), thrombocytopenia (46%), and vomiting (31%). The most prevalent grade ≥ 3 TEAE were neutropenia (46%), anemia (31%), leukopenia (17%), and fatigue (9 %). Partial responses (PR) were noted in 4 pts (13%); 10 pts (32%) achieved stable disease for > 4 months for a clinical benefit rate (CBR) of 45%. 16 pts (47%) had prior exposure to a taxane, including 1 pt who achieved PR. Among 24 evaluable pts with ovarian cancer, response rate was 17%, CBR was 58%, and PFS was 6.83 months (95% CI 3.73, not reached (NR)). Median duration of clinical benefit in ovarian cancer was 7.57 months (95% CI: 4.43, NR). Conclusions: Oral selinexor in combination with weekly paclitaxel demonstrated promising clinical activity with manageable toxicity, and further evaluation with once weekly selinexor is warranted. This combination should be considered for further exploration in a randomized study, especially in ovarian malignancies. Clinical trial information: NCT02419495.

scholarly journals Risk Algorithm Using Serial Biomarker Measurements Doubles the Number of Screen-Detected Cancers Compared With a Single-Threshold Rule in the United Kingdom Collaborative Trial of Ovarian Cancer Screening

2015 ◽  
Vol 33 (18) ◽  
pp. 2062-2071 ◽  
Author(s):  
Usha Menon ◽  
Andy Ryan ◽  
Jatinderpal Kalsi ◽  
Aleksandra Gentry-Maharaj ◽  
Anne Dawnay ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
United Kingdom ◽  
Cancer Screening ◽  
Ca 125 ◽  
Ovarian Cancer Screening ◽  
Collaborative Trial ◽  
The United Kingdom ◽  
Risk Algorithm ◽  
The Impact ◽  
Threshold Rule

Purpose Cancer screening strategies have commonly adopted single-biomarker thresholds to identify abnormality. We investigated the impact of serial biomarker change interpreted through a risk algorithm on cancer detection rates. Patients and Methods In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, 46,237 women, age 50 years or older underwent incidence screening by using the multimodal strategy (MMS) in which annual serum cancer antigen 125 (CA-125) was interpreted with the risk of ovarian cancer algorithm (ROCA). Women were triaged by the ROCA: normal risk, returned to annual screening; intermediate risk, repeat CA-125; and elevated risk, repeat CA-125 and transvaginal ultrasound. Women with persistently increased risk were clinically evaluated. All participants were followed through national cancer and/or death registries. Performance characteristics of a single-threshold rule and the ROCA were compared by using receiver operating characteristic curves. Results After 296,911 women-years of annual incidence screening, 640 women underwent surgery. Of those, 133 had primary invasive epithelial ovarian or tubal cancers (iEOCs). In all, 22 interval iEOCs occurred within 1 year of screening, of which one was detected by ROCA but was managed conservatively after clinical assessment. The sensitivity and specificity of MMS for detection of iEOCs were 85.8% (95% CI, 79.3% to 90.9%) and 99.8% (95% CI, 99.8% to 99.8%), respectively, with 4.8 surgeries per iEOC. ROCA alone detected 87.1% (135 of 155) of the iEOCs. Using fixed CA-125 cutoffs at the last annual screen of more than 35, more than 30, and more than 22 U/mL would have identified 41.3% (64 of 155), 48.4% (75 of 155), and 66.5% (103 of 155), respectively. The area under the curve for ROCA (0.915) was significantly (P = .0027) higher than that for a single-threshold rule (0.869). Conclusion Screening by using ROCA doubled the number of screen-detected iEOCs compared with a fixed cutoff. In the context of cancer screening, reliance on predefined single-threshold rules may result in biomarkers of value being discarded.

Correlation of CA-125 and RECIST evaluation in recurrent ovarian cancer (ROC): Results from a randomized phase III study of trabectedin (T) with pegylated liposomal doxorubicin (PLD) versus PLD alone

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5550-5550
Author(s):  
T. J. Herzog ◽  
J. B. Vermorken ◽  
E. Pujade-Lauraine ◽  
J. Li ◽  
E. Bayever ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Predictive Value ◽  
Objective Response ◽  
Pegylated Liposomal Doxorubicin ◽  
Phase Iii ◽  
Ca 125 ◽  
Open Label ◽  
Significant Prolongation ◽  
Phase Iii Study ◽  
The Impact

5550 Background: OVA-301, an open-label, multicenter, randomized phase III study comparing the combination of T and PLD to PLD alone in 672 ovarian cancer patients, showed significant prolongation in Progression-Free Survival (PFS) and higher Objective Response (OR) in the combination arm (T-PLD) by three separate assessments, investigator assessment (IA), independent radiology (IR) and oncology review (IO). The purpose of this analysis is to examine: 1) the impact of early changes in CA-125 over the subsequent best OR by RECIST; 2) the concordance between best OR determined by CA-125 and RECIST; 3) the value of CA-125 to predict radiological response. Methods: Tumor assessments by imaging and CA-125 were performed at baseline, and every 8 weeks during study in both arms. Radiological tumor assessment, regardless of CA-125 changes, determined the study conduct. Early CA-125 changes were those assessed at the first and second evaluation. Analyses were based on “all randomized patients.” Results: Response rate by RECIST (IR)/CA-125 was 28%/48% for T-PLD vs. 19%/33% for PLD. The association between CA-125 and RECIST response was stronger for IA relative to IR/IO, with 79% concordance for both arms, 65% overall positive predictive value (PPV) and 89% negative predictive value (NPV) for IA and 74%/75% concordance, 46%/49% PPV and 93%/92% NPV for IR/IO. Early CA-125 changes were assessed in 514 patients. Early ≥25% CA-125 decreases in the first/second evaluation occurred in 85%/95% of RECIST responders in the T-PLD arm and in 81/82% responders treated with PLD. Conclusions: The predictive value of CA-125 response was high and similar in both arms. The addition of T to PLD resulted in superior efficacy in this patient population as assessed by IA, IR and IO, with a favorable trend for CA-125 response assessment. RECIST response was preceded by a significant CA-125 decrease in a high proportion of patients. [Table: see text]

Examining screening behaviors at a high-risk ovarian cancer clinic.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13047-e13047
Author(s):  
Courtney Lynam-Scherr ◽  
Kisha T Hope ◽  
Irene B. Helenowski ◽  
Masha Kocherginsky ◽  
Melissa Keene ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
High Risk ◽  
Insurance Coverage ◽  
Prophylactic Surgery ◽  
Ca 125 ◽  
Ovarian Cancer Risk ◽  
Race Ethnicity ◽  
The Impact ◽  
Screening Behaviors ◽  
High Risk Clinic

e13047 Background: Women with deleterious BRCA1/2mutations have a significantly increased lifetime risk to develop ovarian cancer. Prophylactic surgery can significantly reduce ovarian cancer risk. The Northwestern Ovarian Cancer Early Detection and Prevention Program (NOCEDPP) was established to monitor this high-risk population prior to risk-reducing surgery. For such patients, providers in the NOCEDPP recommend screening with CA-125 and transvaginal ultrasound (TVUS) biannually. The aim of this study was to examine screening rates of women who have not had surgery but attend the NOCEDPP. Methods: We reviewed electronic health records of 1,662 women who attended the NOCEDPP clinic between October 2005 – October 2015. Demographic and clinical characteristics and utilization of screening were analyzed retrospectively using descriptive statistics and Kruskal-Wallis H-tests to examine differences in screening rates by age, race, ethnicity and insurance type. Results: Of the 1,662 women initially identified, 385 had a known BRCA mutation, 303 had an appointment with at least 6 months between first and last procedure – the sample included in the final analysis. Compared with women ages 35-45 (median = 1.91) and 45+ (median = 1.18), women ages 20-35 attended the most screenings per year (median = 2.12) p = 0.001, a rate consistent with biannual recommendations. There were no significant differences in screening rate by race, ethnicity, or insurance coverage. Conclusions: Despite changes in national guidelines, providers in our high-risk clinic continue to recommend CA-125 and TVUS biannually. Our preliminary data indicates patients’ attendance is uninfluenced by race, ethnicity, or insurance coverage. Further exploration of the impact of age is warranted. Implication of findings indicate a high-risk clinic may positively impact screening behaviors above and beyond factors typically associated with non-adherence.

scholarly journals 531 A Phase 1b multi-tumor cohort study of cabozantinib plus atezolizumab in advanced solid tumors: results of the triple-negative breast cancer, ovarian cancer, and endometrial cancer cohorts

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A562-A562
Author(s):  
Ira Winer ◽  
Akhila Wimalasingham ◽  
Joaquina Baranda ◽  
Armando Santoro ◽  
Kristen Spencer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Endometrial Cancer ◽  
Solid Tumors ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Prior Therapy ◽  
Phase 1B

BackgroundCabozantinib, a multiple receptor tyrosine kinase inhibitor, promotes an immune-permissive environment which might enhance the activity of immune checkpoint inhibitors. COSMIC-021 (NCT03170960), a multicenter phase 1b study, is evaluating the combination of cabozantinib with atezolizumab in advanced solid tumors; here we present efficacy and safety results in patients with triple negative breast cancer (TNBC), ovarian cancer (OC), and endometrial cancer (EC).MethodsEligible patients had locally advanced or metastatic TNBC, OC, or EC and had radiographically progressed on prior systemic anticancer therapy. One or two lines of prior therapy were permitted. Patients with OC were platinum resistant or refractory. Prior treatment with anti-PD-1 or anti-PD-L1 agents was allowed for patients with TNBC. Patients received cabozantinib, 40 mg PO QD, plus atezolizumab, 1200 mg IV Q3W. The primary endpoint was objective response rate (ORR) per RECIST 1.1 as assessed by investigator. Other endpoints included safety, duration of response (DOR), progression free survival (PFS), and overall survival (OS). CT/MRI scans were performed Q6W for the first year and Q12W thereafter.ResultsAs of February 19, 2021, 30–32 patients were enrolled in each of the cohorts. 47% of patients with TNBC, 47% with OC, and 40% with EC had received 2 lines of prior therapy. Median follow-up was 18.7 months, 20.8 months, and 19.0 months for the TNBC, OC, and EC cohorts, respectively. Grade 3/4 treatment-related adverse events occurred in 33% of patients with TNBC, 56% with OC, and 37% with EC. One Grade 5 treatment-related adverse event of pulmonary hemorrhage occurred in the TNBC cohort and one of encephalitis occurred in the OC cohort. Cabozantinib plus atezolizumab demonstrated clinical activity in all three tumor cohorts (table 1).Abstract 531 Table 1ConclusionsCabozantinib in combination with atezolizumab demonstrated encouraging clinical activity in patients with previously treated advanced cancers.AcknowledgementsMedical writing support provided by Suvajit Sen, PhD (Exelixis, Inc.)Trial RegistrationNCT03170960Ethics ApprovalYesConsentYes

scholarly journals ONC212 Is a Potent Member of the Imipridone Class of Anti-Cancer Compounds That Induces p53-Independent Apoptosis in Hematological Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4059-4059
Author(s):  
Takenobu Nii ◽  
Jo Ishizawa ◽  
Ran Zhao ◽  
Jianfang Zeng ◽  
Dhruv Chachad ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Cell Lines ◽  
Research Funding ◽  
Time Course ◽  
Protective Factor ◽  
Hematological Malignancies ◽  
Human Tumor ◽  
Protein Translation ◽  
Clinical Activity ◽  
Anti Cancer

Abstract The functional or genetic inactivation of p53 hampers human tumor treatment. Therefore, novel therapeutic strategies are needed. ONC201 is a p53-independent inducer of apoptosis that is the founding member of the imipridone class of novel anti-cancer compounds, which possess a unique pharmacophore. We discovered that ONC201 exerts anti-tumor effects via ATF4 induction through activation of an atypical integrated stress response (ISR) (Ishizawa et al. and Kline et al, Sci Signal, 2016). Several clinical trials of ONC201 are ongoing in advanced cancers, showing a promising safety profiling and signs of clinical activity in both solid tumors and hematopoietic malignancies. In this study, we investigated the effects of ONC212, which has emerged as a highly potent member of the imipridone family, in preclinical models of hematological malignancies. ONC212 exerted potent and prominent apoptogenic effects on acute myeloid leukemia (AML) and mantle cell lymphoma (MCL) cell lines (e.g., ED50s of 141.0 nM in p53 wild-type OCI-AML3 cells, 105.7 nM in MOLM13 cells, and 265.2 nM in p53-null JeKo-1 cell lines). Time course analysis of apoptosis in OCI-AML3 cells showed that ONC212 takes more than 36 hours to start to induce apoptosis, which is similar to observations with ONC201. Next, we further examined similarities between ONC212 and ONC201 by evaluating the in vitro efficacy of ONC212 in ONC201-resistant (ONC201-R) cell lines that we have generated by chronic exposure of MCL and AML cell lines to ONC201, of which ED50s for ONC201 treatment at 72 hrs were all > 5 μM. Interestingly, the ONC201-R cell lines were more resistant to ONC212 than the isogenic ONC201-naïve cells (Figure 1), indicating that these cell lines are cross-resistant to ONC212. We previously proved that increased protein translation of the transcription factor ATF4 is one of the major molecular events involved in ONC201-induced apoptosis (Ishizawa et al., Sci Signal, 2016). Similarly, ATF4 protein abundance was increased by 24-hour treatment with ONC212. DDIT3 (CHOP) gene, a target of ATF4, was transcriptionally upregulated in parallel with its target genes GADD34, DR5 and TRIB3 in ONC212-treated JeKo-1 and OCI-AML3 cells by 24 hrs after treatment (Figure 2). Of note, ONC201 was reported to transcriptionally induce TRAIL in a p53-independent manner in solid tumors (Allen et al., Sci Transl Med, 2013), but it was not operational in hematological cell lines (Ishizawa et al., Sci Sig 2016). Consistently, we also confirmed that ONC212 does not increase TRAIL mRNA in MCL (JeKo-1) and AML (OCI-AML3) cells. BCL-2 is a protective factor for cells under endoplasmic reticulum stress, which is one way to activate ISR. Therefore, we investigated whether the BCL-2 inhibitor ABT-199 sensitizes hematopoietic malignant cells to ONC212. Apoptosis was significantly higher in the combination than either drug alone in MCL and AML cell lines even in THP-1 and OCI-AML3 cells that are relatively resistant to ONC201/212 and/or ABT-199 (Figure 3), suggesting that this combination could overcome the resistance to either of agents. Indeed, the combination was also synergistic in the OCI-AML3 ONC201-R cell line (Figure 3). Taken together, our preclinical studies suggest that ONC212 is a promising and potent new member of the impridone class of anti-cancer compounds that warrants further development in hematological malignancies. The combination of ONC212 with ABT-199 is attractive, considering that acquired resistance after a short-term response remains a clinical challenge with ABT-199. Disclosures Konopleva: AbbVie: Research Funding; Genentech: Research Funding. Allen:Oncoceutics Inc.: Employment. Stogniew:Oncoceutics Inc.: Employment, Equity Ownership. Andreeff:Oncoceutics Inc.: Membership on an entity's Board of Directors or advisory committees.

A first-in-human phase I study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2500-2500 ◽  
Author(s):  
Geoffrey Shapiro ◽  
Lee S. Rosen ◽  
Anthony W. Tolcher ◽  
Jonathan Wade Goldman ◽  
Leena Gandhi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Antitumor Activity ◽  
Advanced Cancer ◽  
Human Cancer ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Ca 125 ◽  
Clinical Activity

2500 Background: Cyclin dependent kinases 4 and 6 (CDK4/6) act with D-type cyclins to inactivate the retinoblastoma (Rb) tumor suppressor protein and enable cell cycle progression from G1 to S phase. LY2835219 is a selective inhibitor of CDK4/6 that shows antitumor activity in preclinical models of human cancer and also distributes efficiently to the brain. We performed a phase 1 study to evaluate safety, pharmacokinetics, pharmacodynamics, and antitumor activity of LY2835219. Methods: 3+3 dose escalation was followed by expansions in 5 tumor types (brain metastases permitted): non-small cell lung cancer (NSCLC), glioblastoma, breast cancer, melanoma, and colorectal cancer. LY2835219 was taken orally every 12 or 24 hours (in escalation) and every 12 hours (in expansions) on days 1-28 of a 28-day cycle. Results: 55 patients (pts) received LY2835219. In escalation, 33 pts received LY2835219 on 1 of 2 schedules: 50, 100, 150, 225 mg every 24 hours (Q24H) or 75, 100, 150, 200, 275 mg every 12 hours (Q12H). On the Q24H schedule, the maximum tolerated dose (MTD) was not identified. On the Q12H schedule, the MTD was 200mg Q12H with dose limiting toxicity of G3 fatigue at 200 mg (1/6 evaluable pts) and 275 mg (2/3 evaluable pts). At 200mg Q12H, the mean Cmax and AUC0-24hr at steady state were 285 ng/mL and 5502 ng-hr/ml, respectively. In skin, LY2835219 induced pharmacodynamic inhibition of both Rb phosphorylation and topoisomerase IIα expression. In the ongoing expansions, 22 pts have received LY2835219. Across the study, the most common related adverse events were diarrhea (52%, including 5% G3), nausea (30%, 4% G3), fatigue (21%, 7% G3), vomiting (18%, 2% G3), and neutropenia (16%, 7% G3). 15 pts have reached ≥4 cycles for stable disease or better with 3 pts achieving 8, 16, and 26 cycles. One pt with ovarian cancer had a durable CA-125 response with >50% decrease for 16 cycles. One pt with KRAS mutant NSCLC had a 27% decrease by RECIST. One pt with CDKN2A-/- NRAS mutant melanoma had a confirmed partial response. Early clinical activity has been observed in ovarian cancer, NSCLC, breast cancer, and melanoma. Conclusions: LY2835219 shows acceptable safety and early clinical activity as a single agent for patients with advanced cancer. Clinical trial information: NCT01394016.

A phase Ib/II, multicenter, open-label study of DSP-7888 dosing emulsion in combination with immune checkpoint inhibitors (CPI) nivolumab or pembrolizumab in adult patients (pts) with advanced solid tumors, including platinum-resistant ovarian cancer (PROC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS6099-TPS6099
Author(s):  
Makoto Origuchi ◽  
Chris Korth ◽  
Zhonggai Li ◽  
Edgar E. Braendle
Keyword(s):  
Ovarian Cancer ◽  
Solid Tumors ◽  
Phase Ii ◽  
Metastatic Cancer ◽  
Objective Response ◽  
Clinical Activity ◽  
Induction Phase ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase Ib

TPS6099 Background: DSP-7888 is a therapeutic cancer vaccine composed of two synthetic peptides derived from Wilms’ tumor 1 (WT1) to promote both cytotoxic and helper T-lymphocyte-mediated immune responses against WT1-expressing tumors. WT1 is overexpressed in various solid tumors, including ovarian cancer. Combining cancer vaccines like DSP-7888 with a CPI may reduce resistance to immunomodulators and improve clinical benefit. A phase Ib/II study is being conducted to evaluate DSP-7888 in combination with a CPI in pts with advanced solid tumors, including PROC (NCT03311334). Methods: This phase Ib/II, open-label, multicenter, two-part dose-search/dose-expansion study investigates DSP-7888 + nivolumab or pembrolizumab in pts with advanced solid tumors (phase Ib), including PROC (phase II). The phase Ib primary objectives are safety, tolerability, and identification of the recommended phase II dose (RP2D). The phase II primary objective is evaluation of objective response rate (ORR); secondary objectives are clinical activity, safety, and tolerability. Pts aged ≥18 years with unresectable, metastatic cancer approved for treatment with nivolumab (phase Ib, Arm 1, n=6–12, 7 enrolled) or pembrolizumab (phase Ib, Arm 2, n=6–12, 6 enrolled), or with PROC (phase II) are eligible. Phase II will enroll ~40 pts into two groups based on programmed death-ligand 1 status (combined positive score of ≥10 [Group 1] or <10 [Group 2]). Clinical activity will be assessed continuously using Bayesian analysis and actual enrollment may increase by ~20 pts/group based on this analysis. Pts in phase II will receive DSP-7888 intradermally (RP2D from phase Ib) once a week (wk) for 6 wks in the induction phase then every 3 wks in the maintenance phase. Beginning Day 1, pembrolizumab will be administered intravenously every 3 wks. In phase II, objective disease will be assessed every 6 wks for 24 wks, then every 12 wks until progression. Endpoints include ORR (per RECIST v1.1) (primary), duration of response, disease control rate (DCR), progression-free survival (PFS), 6-month PFS rate (per RECIST v1.1), and overall survival, immune (i)ORR, iDCR, and iPFS (per iRECIST) (secondary). Exploratory endpoints include blood and tumor tissue biomarkers. Safety and tolerability, assessed by adverse events, will be evaluated throughout the duration of the study and follow-up. This study is currently recruiting patients. Clinical trial information: NCT03311334.

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