scholarly journals Clinical Efficacy of Olaparib in IDH1/IDH2-Mutant Mesenchymal Sarcomas

2021 ◽  
pp. 466-472
Author(s):  
Joseph P. Eder ◽  
Deborah B. Doroshow ◽  
Khanh T. Do ◽  
Vicki L. Keedy ◽  
Jeffrey S. Sklar ◽  
...  
Keyword(s):  
Stable Disease ◽  
Clinical Benefit ◽  
Objective Response ◽  
Parp Inhibitors ◽  
Epithelioid Hemangioendothelioma ◽  
Parp Inhibition ◽  
Open Label ◽  
Open Label Study ◽  
Recombination Repair ◽  
Pulmonary Epithelioid Hemangioendothelioma

PURPOSE Tumors with neomorphic mutations in IDH1/2 have defective homologous recombination repair, resulting in sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition. The Olaparib Combination trial is a phase II, open-label study in which patients with solid tumors harboring IDH1/2 mutations were treated with olaparib as monotherapy, with objective response and clinical benefit rates as the primary end points. METHODS Ten patients with IDH1/2-mutant tumors by next-generation sequencing were treated with olaparib 300 mg twice daily. RESULTS Three of five patients with chondrosarcomas had clinical benefit, including one patient with a partial response and two with stable disease lasting > 7 months. A patient with pulmonary epithelioid hemangioendothelioma had stable disease lasting 11 months. In contrast, clinical benefit was not observed among four patients with cholangiocarcinoma. CONCLUSION These results indicate preliminary activity of PARP inhibition in patients with IDH1/2-mutant chondrosarcoma and pulmonary epithelioid hemangioendothelioma. Further studies of PARP inhibitors alone and in combination in this patient population are warranted.

PULSE: A randomized phase II open label study of panitumumab rechallenge versus standard therapy after progression on anti-EGFR therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS143-TPS143
Author(s):  
John H. Strickler ◽  
Fang-Shu Ou ◽  
Tanios S. Bekaii-Saab ◽  
Christine Megerdichian Parseghian ◽  
Andrea Cercek ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Benefit ◽  
Objective Response ◽  
Progression Free Survival ◽  
Wild Type ◽  
Open Label ◽  
Genomic Alterations ◽  
Open Label Study ◽  
Label Study ◽  
Randomized Phase Ii

TPS143 Background: Patients with KRAS and NRAS ( RAS) wild-type mCRC benefit from the epidermal growth factor receptor (EGFR) monoclonal antibodies (Abs) panitumumab and cetuximab, but nearly all patients experience resistance. Blood-based profiling of cell free DNA (cfDNA) can identify genomic alterations that drive acquired EGFR Ab resistance. After discontinuation of anti-EGFR Abs, acquired genomic alterations decay over time to undetectable levels. Some studies have suggested clinical benefit from EGFR Ab rechallenge, but there is limited evidence that EGFR Ab rechallenge improves survival compared to standard of care (SOC) therapies. We hypothesize that cfDNA profiling will identify patients appropriate for panitumumab rechallenge, and that these molecularly selected patients will have improved survival compared to current SOC therapies. Methods: This is a randomized phase II, open label study designed to compare the overall survival (OS) of panitumumab rechallenge versus SOC (investigator choice TAS-102 or regorafenib). Secondary objectives include comparisons of progression free survival, objective response rate, clinical benefit rate, and quality of life as measured by the linear analogue self-assessment (LASA) questionnaire. Eligible patients have radiographically measurable KRAS, NRAS, and BRAF codon 600 wild-type mCRC based on tumor tissue testing, and must have experienced progression or intolerance to treatment with a fluoropyrimidine, oxaliplatin, irinotecan, an anti-VEGF Ab, and an anti-PD-1 Ab if the tumor has mismatch repair deficiency or is MSI-H. Progression after at least 4 months treatment with an anti-EGFR Ab is required. All patients must be enrolled in the COLOMATE cfDNA screening protocol (NCT03765736) and meet molecular eligibility based on Guardant360 cfDNA profiling (absence of amplification of ERBB2, KRAS, NRAS, and MET; absence of mutations of BRAF, EGFR, ERBB2, KRAS, NRAS, and MET [mutant allele frequency > 0.5%]). Greater than 90 days must have elapsed between the most recent treatment with an anti-EGFR Ab and cfDNA profiling. Dosing for all study drugs is according to clinical SOC. 120 patients will be randomized 1:1 to panitumumab rechallenge or SOC. With 83 OS events, this study will have 80% power to detect an improvement in median OS from 6.5 to 10 months (HR=0.65; 1-sided α= 0.15). This study began enrollment in 6/2020. Recruitment is ongoing at 16 sites in the Academic and Community Cancer Research United (ACCRU) network (ACCRU-GI-1623). Clinical trial information: NCT03992456.

Phase Ib/II open-label, randomized evaluation of atezolizumab (atezo) + Imprime PGG (Imprime) + bevacizumab (bev) vs regorafenib (rego) in MORPHEUS: Microsatellite-stable (MSS) metastatic colorectal cancer (mCRC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3559-3559
Author(s):  
Marwan Fakih ◽  
James M. Cleary ◽  
Yong Sang Hong ◽  
Tae-You Kim ◽  
Rachael A Safyan ◽  
...  
Keyword(s):  
Stable Disease ◽  
Checkpoint Inhibitors ◽  
Macrophage Polarization ◽  
Objective Response ◽  
Systemic Exposure ◽  
Progression Free Survival ◽  
Open Label ◽  
Multikinase Inhibitor ◽  
Phase Ib ◽  
M1 Macrophage

3559 Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to identify early efficacy and safety signals of treatment (tx) combinations across cancers. Here, atezo (anti-PD-L1) was tested with Imprime and bev (anti-VEGF) for MSS mCRC, a poorly immunogenic cancer generally resistant to checkpoint inhibitors. Imprime acts as a pathogen-associated molecular pattern that, when bound to anti-β glucan antibodies (ABA), activates the innate immune system with the potential to 1) promote priming and expansion of tumor-specific T cells, 2) promote M2-M1 macrophage polarization and 3) enhance the immunomodulatory effects of atezo and bev. Therefore, we hypothesized that atezo + Imprime + bev would induce an antitumor response beyond that of rego, a standard-of-care multikinase inhibitor, in patients (pts) with MSS mCRC. Methods: Pts with MSS mCRC unselected for the Imprime-specific biomarker (ABA) and refractory to 1-2 prior lines of standard therapy received atezo (1200 mg IV every 3 weeks [q3w]) + Imprime (4 mg/kg IV on Days 1, 8, 15) + bev (7.5 mg/kg IV q3w) or control tx with rego (160 mg orally days 1-21; dose escalation to 160 mg during Cycle 1 allowed per institutional guidelines). The primary endpoint was objective response rate (ORR; investigator-assessed RECIST 1.1); secondary endpoints included disease control rate (DCR; response or stable disease ≥ 12 weeks), progression-free survival (PFS), overall survival (OS) and safety. Results: Pts were followed-up for ≥18 wk. 15 pts received atezo + Imprime + bev and 13 received rego. Grade (Gr) 3/4 tx-related adverse events (TRAEs) were seen in 13% of atezo + Imprime + bev and 62% of rego pts. No Gr 5 AEs occurred in atezo + Imprime + bev pts and 1 (8%) was reported in a rego pt. One pt in each arm (7% vs 8%, respectively) withdrew from tx due to a TRAE. No radiological responses were seen in either arm. Five pts (33%) receiving atezo + Imprime + bev and 8 (62%) receiving rego had stable disease as best response. DCR was 13% with atezo + Imprime + bev and 23% with rego. Median PFS was 1.5 mo (95% CI: 1.4, 2.8) and 2.8 mo (95% CI: 1.6, 3.1), and median OS was 5.7 mo (95% CI: 4.4, 10.5) and 10.2 mo (95% CI: 4.8, NE) with atezo + Imprime + bev and rego, respectively. There was no apparent correlation between baseline PD-L1 expression or CD8+ lymphocyte tumor infiltration and clinical benefit. Further, the systemic exposure of atezo, Imprime and bev and immunogenicity of atezo and bev are in line with previous clinical experience. Additional biomarker, pharmacokinetics and anti-drug antibody data will be shown. Conclusions: Atezo + Imprime + bev was well tolerated; toxicities were consistent with the safety profiles of the individual agents. No efficacy signal was identified with atezo + Imprime + bev in pts with MSS refractory mCRC. Clinical trial information: NCT03555149.

GSK3β Inhibition Synergizes with PARP Inhibitors through the Induction of Homologous Recombination Deficiency in Colorectal Cancer

2020 ◽  
Author(s):  
Ning Zhang ◽  
Yu-Nan Tian ◽  
Li-Na Zhou ◽  
Meng-Zhu Li ◽  
Shan-Shan Song ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Homologous Recombination ◽  
High Throughput Screening ◽  
Glycogen Synthase ◽  
Objective Response ◽  
Xenograft Model ◽  
Parp Inhibitors ◽  
High Rate ◽  
Parp Inhibition ◽  
Mouse Xenograft Model

Abstract Background: Monotherapy with poly ADP-ribose polymerase (PARP) inhibitors results in limited objective response rate (≤ 60% in most cases) in patients with homologous recombination repair (HRR)-deficient cancer, which suggests a high rate of resistance in this subset of patients to PARP inhibitors (PARPi). To overcome resistance to PARPi and to broaden their clinical use, we performed high-throughput screening of 99 anticancer drugs in combination with PARPi to identify potential therapeutic combinations. Methods: The effects of PARPi combined with glycogen synthase kinase 3 (GSK3) inhibitors were investigated in vitro with respect to cell viability, cell cycle and apoptosis. The synergy was assessed by calculation of the combination index (CI). GSK3α null and GSK3β null cells were generated using CRISPR/Cas9 technique. The underlying mechanism was examined by western blotting, flow cytometry, qRT-PCR and fluorescence microscopy. This combination was also evaluated in the mouse xenograft model; tumor growth and tumor lysates were analyzed, and the immunohistochemistry assay was performed. All data are presented as mean ± SD. Comparison between two groups was performed with the Student’s t-test.Result: The data showed that ~25% of oncological drugs and kinase inhibitors that were evaluated displayed synergy with PARPi in HCT-15 cells. Among the tested agents, GSK3 inhibitors (GSK3i) exhibited the strongest synergistic effect with PARPi. Moreover, the synergistic antitumor effect of GSK3 and PARP inhibition was confirmed in a panel of colorectal cancer (CRC) cell lines with diverse genetic backgrounds. Additionally, inhibition or genetic depletion of GSK3β was found to impair HRR of DNA and reduce the mRNA and protein level of BRCA1. Finally, we demonstrated that inhibition or depletion of GSK3β could enhance the in vivo sensitivity to simmiparib without toxicity.Conclusion: Our results provide a mechanistic understanding of combination of PARP and GSK3 inhibition, and support the clinical development of this combination therapy for CRC patients.

A Multicenter, Single-Arm, Open-Label Study To Evaluate the Efficacy and Safety of Single-Agent Lenalidomide in Patients with Relapsed and Refractory Multiple Myeloma; Prelininary Results.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1565-1565 ◽  
Author(s):  
Paul Richardson ◽  
Sundar Jagannath ◽  
Mohamad Hussein ◽  
James Berenson ◽  
Seema Singhal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Stable Disease ◽  
Single Agent ◽  
Phase 2 ◽  
Open Label ◽  
Open Label Study ◽  
Label Study ◽  
Multicenter Phase ◽  
Best Response

Abstract INTRODUCTION: Lenalidomide (REVLIMID®; CC-5013) is a novel, orally active immunomodulatory drug under investigation for the treatment of multiple myeloma (MM). Phase 1 dose-escalation studies in patients (pts) with relapsed and refractory MM determined that the maximum tolerated dose (MTD) of lenalidomide was 25 mg/day, based upon myelosuppression encountered beyond 28 days, which was manageable with growth factor support and dose reduction. In a multicenter phase 2 study to determine optimal dose and schedule, 102 pts with relapsed or refractory MM were randomized to receive lenalidomide at either 15 mg bid (n=34) or 30 mg qd (n=68), for 21 days every 4 wks. Both treatment arms showed significant activity with manageable toxicity. An increased incidence of cytopenia was noted in the 15-mg bid group and thus the 30 mg qd schedule was taken forward. METHODS: The objective of this multicenter, phase 2, open-label study (CC-5013-MM-014) was to further evaluate the effectiveness and safety of single-agent lenalidomide administered at a dose of 30 mg qd for 21 days every 28 days (28-day cycle) in pts with relapsed and refractory MM. Eligible patients included those who had received prior thalidomide, bortezomib, or SCT. RESULTS: 222 pts were enrolled into the study. All patients had received at least 2 prior anti-myeloma treatments, including bortezomib (41%), thalidomide (80%), and SCT (44%). Table 1 shows Best Response data, excluding patients in whom responses were not evaluable (n=10). Partial response or better occurred in 25% of patients and SD or better in 71%. Time to Progression was a median of 22.4 wks (range 1.8– 66 wks). The median survival has not been reached (the lower bound of the 95% CI exceeds 15 months). The most common treatment-related AEs (those reported in ≥10% of patients overall) included upper respiratory tract infection, neutropenia and thrombocytopenia. AEs that most frequently led to dose reduction or interruption by percentage of cases were neutropenia (40%), thrombocytopenia (23%), fatigue (5%), and anemia (5%). CONCLUSION: Oral lenalidomide in relapsed and refractory MM patients achieved PR+CR in 25%, stable disease or better in 71%, a median TTP of approximately 6 months and a median survival that has not been reached. Toxicity has been manageable with a very low incidence of DVT and minimal treatment-emergent neuropathy. Table 1. Best Response Best Response* n (%) *Excluding patients not evaluable (n=10); CR=complete response and PR=partial response (EBMT criteria) ≥PR (CR + PR) 53 (25) Stable disease 152 (71)

A phase II, multicenter, open-label study of YM155 plus docetaxel in subjects with stage III (unresectable) or stage IV melanoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8587-8587 ◽  
Author(s):  
Joyce Leta Steinberg ◽  
Agop Y. Bedikian ◽  
D. Scott Ernst ◽  
Bartosz Chmielowski ◽  
Bruce Redman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Continuous Infusion ◽  
Primary Endpoint ◽  
Clinical Benefit ◽  
Response Rate ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Open Label ◽  
Clinical Benefit Rate

8587 Background: Survivin is a microtubule-associated protein implicated in both preservation of cell viability and regulation of mitosis in tumor cells. It is over-expressed in melanoma, breast, and non-Hodgkin’s lymphoma. YM155 is a first in class survivin inhibitor. Methods: The study had 2 parts: Part 1 established the dose of docetaxel that was tolerable in combination withYM155 at 5 mg/m2/day continuous infusion over 168 hours q 3 weeks. Part 2 utilized the dose of docetaxel established in Part 1 to further evaluate the tolerability and activity of the combination. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints were overall response rate, 1-year overall survival (OS), time from first response to progression, clinical benefit rate, time to response, and safety. Results: 64 patients with metastatic melanoma were treated with docetaxel followed by continuous infusion YM155. 7 patients were treated with 100mg/m2 of docetaxel and 57 patients were treated with 75mg/m2 of docetaxel. Median age was 59, with 44 men and 20 women treated. 6-month PFS per Independent Review Committee (IRC) was 34.8% (95% CI 21.3 – 48.6%). Overall objective response rate per IRC was 12.5%, with no complete responses (CR) and 8 patients with partial responses (PR). The Stable disease (SD) rate was 51.6%, leading to a clinical benefit rate (CR + PR + SD) of 64.1%. Estimated 1-year overall survival is 50.5%. 87.5% of patients experienced a Grade 3 (G3) or Grade 4 (G4) event attributable to either YM155 or docetaxel. The clinically pertinent G3 or 4 toxicities occurring in greater than 5% of patients treated included neutropenia (59.4%), febrile neutropenia (12.5%), mucositis (9.4%), fatigue (7.8%), diarrhea (6.3%), and dehydration (6.3%). There were 3 deaths on study, all attributable to disease progression. Conclusions: YM155 is a novel agent that shows modest activity when combined with docetaxel in patients with melanoma. YM155 was generally well tolerated, but the pre-determined primary endpoint for efficacy was not achieved.

Efficacy and toxicity of immunotherapy with immune checkpoint inhibitors in gynecologic cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18092-e18092
Author(s):  
Michelle Kuznicki ◽  
Amy Joehlin-Price ◽  
Peter Graham Rose ◽  
Haider Mahdi
Keyword(s):  
Stable Disease ◽  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Gynecologic Cancer ◽  
Objective Response ◽  
Complete Response ◽  
Rank Test ◽  
First Line

e18092 Background: There is limited data on outcomes for gynecologic cancer patients treated with immune checkpoint inhibitors (ICI) outside the scope of clinical trials. Here we present our Institutional experience with a cohort of endometrial (EC) and ovarian cancer (OC) treated with ICI. Methods: 59 patients who received ICI were included (23 OC and 36 EC). Progression-free (PFS) and Overall survivals (OS) were determined by Kaplan-Meier (KM) curve and log rank test. Comparison of duration of response (DOR) and stable disease (DOSD) was done with unpaired t-test or one-way ANOVA. Rates of objective response (ORR) including partial response (PR) and complete response (CR), and stable disease (SD) were compared by Fischer’s exact test. Results: Median age was 66 years. 23 patients were microsatellite stable (MSS), 23 microsatellite instability high (MSI-H). Median number of prior lines was 2 (0-11). PFS and OS for EC and OC were overlapping; therefore outcomes for both were combined [(PFS 6.4m OC vs 7.3 m EC, p = 0.61), (OS 15.9 m OC vs 14.2 m EC, p = 0.78)]. Response rates consisted of 20.3% PR, 8.5% CR, 37.3% SD. Differences in responses were noted for clear cell carcinoma (CC) (33.3% PR, 11.1% CR, 33.3% SD) and MSI-H (36.4% PR, 18.2% CR, 22.7% SD) compared to MSS (11.8% PR, 0% CR, 47% SD). MSI-H had higher ORR vs. MSS (54.1% vs 11.8%, p = 0.0078). CC trended toward improved ORR vs. MSS (44.4% vs 11.8%, p = 0.14). PFS was improved for MSI-H vs. MSS (10m v 5.0m, p = 0.03). OS for CC compared to any other histology was improved (NR vs 12.8m respectively, p = 0.009). 5 recurrent MSI-H EC patients received ICI as first line monotherapy. Responses included 4 PR and 1 SD (80% ORR, 100% clinical benefit). PFS was 9.2m (3.3-13.3). 80% remained progression-free at last follow up. Overall, 38.9% experienced toxicity: hypothyroidism (15%), dermatitis (5%), pneumonitis (10%), LFT elevation (2%), amylase/lipase elevation (3%), colitis or diarrhea (5%), uveitis (2%) or nephritis (5%). 10% of patients required discontinuation of ICI secondary to toxicity. Trends for PFS and OS favored improved outcomes in patients with toxicity vs. no toxicity [(PFS 12.9m vs 5.6m, p = 0.07), (OS 22.9m vs 13.1m, p = NS)] respectively. Conclusions: In this study, immunotherapy with ICI outcomes favor MSI-H and CC compared to MSS disease. CC had promising OS compared to other histology types. ICI showed promising efficacy in MSI-H EC with 100% clinical benefit rate in chemonaive patients. First line ICI should be investigated in these patients. Positive correlation between toxicity and outcome is noted and will be further investigated.

Open-label, phase II trial of afatinib, with or without vinorelbine (V), for the treatment of HER2-overexpressing inflammatory breast cancer (IBC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS650-TPS650 ◽  
Author(s):  
Charles Swanton ◽  
Jamie Cromer ◽  
Keyword(s):  
Clinical Efficacy ◽  
Clinical Benefit ◽  
Objective Response ◽  
Xenograft Model ◽  
Resistant Cell ◽  
Her2 Gene ◽  
Her2 Positive ◽  
Open Label ◽  
Eligibility Criteria ◽  
Palpable Mass

TPS650 Background: IBC is an aggressive and rare form of BC (1–6% cases). Despite recent treatment advances, prognosis remains poor, with 3-yr survival rate of 40 vs 85% in non-IBC. IBC commonly lack ER/PR and more frequently harbour HER2 gene amplification (~40%), and EGFR overexpression (~30%) associated with poor prognosis. Recent data reported clinical efficacy of lapatinib, a reversible EGFR/HER2 inhibitor, in trastuzumab (T) naïve/resistant HER2 positive IBC. Afatinib is an irreversible ErbB Family Blocker with preclinical activity in T-resistant cell lines, HER2-positive tumor xenografts and HER2-negative SUM 149 xenograft model derived from an IBC cell line. Its clinical efficacy was shown in heavily pre-treated, HER2-positive metastatic BC pts who progressed after T, with PR in 10% and clinical benefit in 46% of pts. The purpose of this biomarker-driven study is to investigate efficacy and safety of afatinib alone and in combination with V upon progression on afatinib monotherapy and the genomic changes that occur through treatment in pts with T pretreated or naïve HER2-positive IBC. Methods: Pts are recruited in 2 parallel cohorts of 20 pts each: T-naïve and T failure. Key eligibility criteria: histologically-confirmed HER2-positive BC; investigator-confirmed IBC characterized by diffuse erythema and oedema (peau d’orange) while dermal lymphatic emboli or palpable mass are not necessary for diagnosis; no prior anti-HER2 therapy except T in the T failure cohort; no prior V; ECOG 0–2. All pts start afatinib monotherapy (40 mg/d oral) in 4-week cycles (Part A). Upon disease progression, pts may receive afatinib (40 mg/d) + V (IV 25 mg/m2/week) (Part B). Primary endpoint: Clinical Benefit Rate (CR, PR or SD) for ≥6 months. Secondary endpoints: objective response rate, PFS, OS and safety. Endpoints are assessed separately for Part A and Part B. Fresh biopsy and blood samples are taken prior to treatment and upon progression in Part A, to explore predictive markers of response/resistance to afatinib, to describe the IBC population which may benefit most, and for next generation sequencing and proteomic analysis. Enrollment ongoing since Aug 2011.

A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer.

2014 ◽  
Vol 32 (18_suppl) ◽  
pp. LBA5500-LBA5500 ◽  
Author(s):  
Joyce Liu ◽  
William Thomas Barry ◽  
Michael J. Birrer ◽  
Jung-min Lee ◽  
Ronald J. Buckanovich ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase 1 ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Recurrent Ovarian Cancer ◽  
Parp Inhibitors ◽  
Open Label ◽  
Angiogenic Therapy ◽  
Platinum Sensitive

LBA5500 Background: PARP inhibitors and anti-angiogenics are clinically active in recurrent ovarian cancer (OvCa). Preclinical studies suggest these agents can synergize, and a phase 1 study showed that the combination of cediranib (ced) and olaparib (olap) is well-tolerated. We therefore compared the activity of olap alone (Olap) to combined ced and olap (Ced/Olap) in treatment of recurrent platinum-sensitive (plat-sens) high-grade serous (HGS) or BRCA-related OvCa (NCT 01116648). Methods: Patients (pts) across 9 centers were randomized 1:1 in this Ph 2 open label study to Olap (olap 400 mg capsules BID) or Ced/Olap (olap 200 mg capsules BID; ced 30 mg daily), stratified by BRCA status and prior anti-angiogenic therapy. Eligibility included pts with recurrent plat-sens HGS or BRCA-related OvCa. Pts had measurable disease by RECIST 1.1, PS 0 or 1, and the ability to take POs. No prior anti-angiogenics in the recurrent setting or prior PARP inhibitor was allowed. Progression-free survival (PFS) was defined as time from randomization to radiographic progression or death. With a target N=90 pts, the study was powered to detect a hazard ratio (HR) of 1.75 (median PFS 6 vs 10.5 mo). Results: Pts were enrolled from Oct 2011 to Jun 2013: 46 to Olap, 44 to Ced/Olap. 48 pts were known BRCA carriers (25 Olap; 23 Ced/Olap). At a planned interim analysis the DSMB recommended release of data. As of Jan 7, 2014, 41 pts had a PFS event. Median PFS was 9.0 mos for Olap and 17.7 mos for Ced/Olap (HR 2.9, 95% CI 1.5-5.6, p = 0.001). There were 2 complete responses (CR) and 21 partial responses (PR) in pts on Olap (56% objective response rate, ORR) and 3 CRs and 33 PRs in pts on Ced/Olap (84% ORR, p = 0.008). The overall rate of Gr3/4 toxicity was higher for pts on Ced/Olap (70%) than on Olap (7%). Differentially occurring toxicities included fatigue (27% Ced/Olap vs 7% Olap), diarrhea (23% vs 0%), and hypertension (39% vs 0%). Updated efficacy and exploratory subgroup analyses will be presented. Conclusions: Combined Ced/Olap significantly extended PFS and ORR compared to Olap in plat-sens OvCa. Further studies of this oral combination in plat-sens OvCa are warranted. Clinical trial information: NCT01116648.

A phase II study of oraxol in the treatment of unresectable cutaneous angiosarcoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11517-11517 ◽  
Author(s):  
Vinod Ravi ◽  
Michael Wagner ◽  
Tom Wei-Wu Chen ◽  
Herbert H. F. Loong ◽  
Robert Gary Mennel ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Objective Response ◽  
Tumour Response ◽  
Open Label ◽  
Stage Design ◽  
Once Daily ◽  
Open Label Study ◽  
Prior Therapy ◽  
Low Incidence ◽  
Dose Reductions

11517 Background: Oraxol is a combination of oral paclitaxel and a novel oral P-glycoprotein inhibitor, HM30181A. Cutaneous angiosarcomas are highly aggressive malignant tumors with poor prognosis. Currently there is no FDA-approved treatment. Methods: This is an open label study evaluating the activity, safety and tolerability of Oraxol 205mg/m2 administered orally, once daily, for 3 consecutive days per week. Planned treatment is for 25 weeks. Subjects included in this study had not received prior therapy with a taxane and did not have metastatic disease. Tumour response was evaluated at 6 weekly intervals using RECIST and photography. A Simon two stage design was used. Results: 18 of 24 enrolled patients (pts); male/female 11/7; median age 77 years (range 56-93), were evaluable at time of analysis. Subjects were recruited during an 18 month period, from Aug-2018 to Jan-2020. Best objective response rates were: CR 22% (n = 4), PR 11% (n = 2), SD 67% (n = 12), PD 0%. 42% of pts with SD had durability > 13 weeks (range 13-25). Median PFS was 38 weeks. All pts remain alive at time of reporting. Furthermore, 5 pts (28%) who had inoperable lesions were deemed operable after Oraxol and received surgical resection. Oraxol was generally well tolerated. Most common adverse events (AEs) G>3 were: diarrhea (n = 1), fatigue (n = 3), neutropenia (n = 9), leucopenia (n = 5), lymphopenia (n = 5). Serious AEs were G3 pneumonia in 2 subjects and G4 neutropenia in 2 subjects, one of which was febrile. All events fully resolved. Neuropathy was uncommon: n = 2 (G1 = 1 @ day 10, G2 = 1 @ day 64). Dose reductions were recorded in 7 subjects. 2 subjects discontinued treatment due to AEs; both asymptomatic pneumonitis seen on CT, which recovered after discontinuation. Following the initial positive results, the protocol has been amended to change the maximum recruitment of subjects from 25 to 43. Conclusions: Oraxol provides an orally administered treatment option for angiosarcoma, with a high and durable clinical benefit rate (CR + PR+ long SD). It is generally well tolerated even in an older patient population; particularly with respect to the the low incidence of neuropathy compared to IV paclitaxel. Recruitment is ongoing. Clinical trial information: NCT03544567 . [Table: see text]

CA045-001: A phase III, randomized, open label study of bempegaldesleukin (NKTR-214) plus nivolumab (NIVO) versus NIVO monotherapy in patients (pts) with previously untreated, unresectable or metastatic melanoma (MEL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS9601-TPS9601 ◽  
Author(s):  
Nikhil I. Khushalani ◽  
Adi Diab ◽  
Paolo Antonio Ascierto ◽  
James M.G. Larkin ◽  
Shahneen Kaur Sandhu ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Objective Response ◽  
Development Program ◽  
Life Assessment ◽  
Phase Iii ◽  
Open Label ◽  
Phase 3 ◽  
Open Label Study ◽  
Label Study

TPS9601 Background: Standard of care for pts with previously untreated, unresectable or metastatic MEL includes checkpoint inhibitors. Bempegaldesleukin is a CD122-preferential IL-2 pathway agonist designed to provide sustained signaling through the IL-2 βγ receptor to activate and proliferate effector CD8+ T and NK cells over T-regulatory cells in the tumor (Hurwitz ME et al. ASCO GU 2017). In the dose-expansion phase of the phase 1/2 PIVOT-02 trial, bempegaldesleukin + NIVO was well tolerated at the recommended phase 2 dose (RP2D; bempegaldesleukin 0.006 mg/kg IV Q3W + NIVO 360 mg IV Q3W), and previously untreated pts with MEL receiving the RP2D achieved an objective response rate (ORR) of 20/38 (53%) and a complete response of 9/38 (24%) by independent radiology review (Diab A et al. SITC 2018). Presented is the design of the first phase 3 trial in the bempegaldesleukin + NIVO development program in pts with previously untreated, unresectable or metastatic MEL. Methods: This phase 3, randomized, open-label study aims to evaluate the effectiveness, safety, and tolerability of bempegaldesleukin + NIVO (NCT03635983). Eligible pts are ≥12 y with histologically confirmed stage III (unresectable) or stage IV MEL and ECOG PS ≤1 or Lansky PS ≥80% (minors 12-17 y). Pts are ineligible if they have active brain or leptomeningeal metastases, uveal MEL, or a recurrence within 6 mo of completing adjuvant treatment with any approved agent. Pts will be stratified by PD-L1 status (measured using PD-L1 IHC 28-8 pharmDx), BRAF mutation status, and lactate dehydrogenase level, and will be randomized to receive bempegaldesleukin 0.006 mg/kg IV Q3W + NIVO 360 mg IV Q3W or NIVO 360 mg IV Q3W up to 24 mo, or until progression or unacceptable toxicity (N ~ 764). Primary endpoints are ORR and progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints include ORR and PFS by investigator, ORR and PFS by BICR in biomarker population, OS in biomarker population, and safety. Additional endpoints include pharmacokinetics and quality-of-life assessment. Clinical trial information: NCT03635983.

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