A phase (Ph) I/II study of belinostat (Bel) in combination with cisplatin, doxorubicin, and cyclophosphamide (PAC) in the first-line treatment of advanced or recurrent thymic malignancies.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7103-7103 ◽  
Author(s):  
Anish Thomas ◽  
Arun Rajan ◽  
Sean Khozin ◽  
Eva Szabo ◽  
Corey Allan Carter ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Thymic Carcinoma ◽  
Single Agent ◽  
Complete Response ◽  
Chemotherapeutic Agents ◽  
Common Grade ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Dose Levels

7103 Background: Belinostat is a hydroxamic acid histone deacetylase (HDAC) pan-inhibitor with single agent activity in thymic malignancies. PAC has activity against thymic cancers. Synergy between Bel and several chemotherapeutic agents, including P, A, and C, has been demonstrated in preclinical models. Methods: Patients with histologically confirmed, treatment naive advanced thymic malignancies, PS<2, measurable disease, and adequate renal, hepatic and hematopoietic functions were eligible. Ph1 evaluated safety and tolerability of the combination using increasing dose levels (DL) of Bel (1000-2000 mg/m² over 48 h CIVI) and PAC (50/50/500 mg/m² IV/cycle) (3+3 dose escalation schema), administered every 21 days for no more than 6 cycles followed by optional maintenance Bel every 4 weeks. Primary end point of Ph2 is overall response rate (ORR). Results: From March 2010 to January 2012, 13 patients were enrolled [7 thymoma (T), 6 thymic carcinoma (TC); 8 in Ph1 and 5 in Ph2; median age: 49 years (range, 23-76)]. In Ph1, 6 patients were treated at DL1 (Bel 1000 mg/m2+ PAC) and 2 patients at DL2 (Bel 2000 mg/m2+ PAC). Dose Limiting Toxicities were Grade 3 nausea and diarrhea, and Grade 4 neutropenia and thrombocytopenia. Recommended phase II dose (RP2D) was set at DL1. Most common grade 3/4 treatment-related adverse events (AE) were lymphocytopenia (100%), leucopenia (85%), neutropenia (77%) thrombocytopenia (54%), anemia (38%), hypophosphatemia (38%), hypomagnesemia, hypokalemia, elevated AST, prolonged QTc and infusion-catheter related thromboembolic complications (23% each). Outcomes included one complete response (CR; T at DL1), 6 partial responses (PR; 4 T, 2 TC; 4 in Ph1, 2 in Ph2) and 6 stable disease (SD; 2 T, 4 TC; 3 each in Ph1 and Ph2). Four patients previously deemed unresectable underwent surgical resection. Conclusions: Belinostat in combination with PAC has activity in thymic malignancies with a predicable AE profile. ORR was 54% including 33% PR in the TC subgroup. RP2D of the combination has been defined. Accrual to Ph2 part and molecular profiling of patient tumors is ongoing.

scholarly journals Promising Clinical Efficacy and Toxicity Profile of Isatuximab Based Regimens for Treatment of Newly Diagnosed and Relapsed/Refractory Multiple Myeloma: A Systematic Review

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1949-1949
Author(s):  
Zunairah Shah ◽  
Madeeha Shafqat ◽  
Faiza Jamil ◽  
Mustafa Nadeem Malik ◽  
Abdul Rafae ◽  
...  
Keyword(s):  
Median Time ◽  
Median Duration ◽  
Overall Response Rate ◽  
Single Agent ◽  
Phase Ib ◽  
First Response ◽  
Common Grade ◽  
Duration Of Response ◽  
Grade 3 ◽  
Combination Regimens

Abstract Introduction: Despite the recent advancements in the treatment of multiple myeloma (MM), there is a constant need of newer therapies in order to treat the complex issue of the disease relapse and refractory disease. Isatuximab (ISA) is a non-Food and Drug Administration (FDA) anti-CD38 monoclonal antibody that acts through immune cell engagement and direct tumor targeting. We report efficacy & toxicity of ISA in newly diagnosed MM ((NDMM) as well as relapsed, refractory MM (RRMM) patients (pts). Methods: Following Prisma guidelines, we performed a comprehensive literature search on articles published after January 2012 using PubMed, Embase, Cochrane Library, Web of Science and Clinicaltrials.gov. On initial search, 246 articles were found and after a detailed screening, 6 completed and 11 ongoing phase I/II/III studies were included. Results: A total of 249 pts were included. Two hundred thirty-four pts had RRMM while 15 pts had NDMM, overall response rate (ORR) was 37.60% and 87% respectively. In a phase I trial involving 34 pts with RRMM, single-agent ISA (1-20 mg/kg) was given. The median age of pts was 64 years (y) [range (r) = 38-85]. The overall response rate (ORR) was 24% with a partial response (PR) in 18% pts. The most common adverse events (AEs) were nausea (34%), fatigue (49%), fever (29%) and headache (26%) and upper respiratory infection (23%). In a phase II trial, 97 pts with RRMM were stratified into 4 groups. Single-agent ISA [3mg/kg, every 2 week,(Q2W); 10 mg/kg, Q2W - every 4 weeks (Q4W); 10 mg/kg (Q2W), 20 mg/kg (QW-Q2W)] was given. The median age of pts was 62.5 y (r = 38-85). The ORR was 9%, 20%, 29% and 24% respectively. The cumulative ORR was 20.6%. The median time to first response was 1.4 months (M) while the median duration of response was 6.6 M. The most common AEs were nausea (33%), fatigue (30%), diarrhea (26%) and cough (24%). In a phase Ib trial, 57 pts with RRMM were stratified into 5 groups. ISA [3 mg/kg (Q2W); 5 mg/kg (Q2W); 10 mg/kg (Q2W); 10 mg/kg (QW-Q2W); 20 mg/kg (QW-Q2W)] in combination with lenalidomide (R) (25mg), and dexamethasone (D) (40 mg) was given. The median age of pts was 61 y (r = 42-76). The median time since the initial diagnosis was 4 y. The ORR was 33%, 67%, 63%, 50%, and 50% respectively. The cumulative ORR was 56% with complete response (CR) in 3.8 % pts, very good partial response (VGPR) in 32.7 % pts and PR in 19.2 % pts. The progression-free survival (PFS) was 8.5 M (r=4.73-16.59). The most common grade 3 and 4 AEs were neutropenia (60%), lymphopenia (58%), leukopenia (53%), anemia (25%), thrombocytopenia (38%), pneumonia (9%), fatigue (7%), and dyspnea (4%). In another phase Ib trial, 36 pts with RRMM were stratified into 3 groups. ISA (5 mg/kg; 10 mg/kg, 20 mg/kg) in combination with pomalidomide (P) (4 mg), and D (40 mg) was given. The ORR was 63%, 55%, and 50% respectively. The cumulative ORR was 55.5%. The median time to first response was 4.1 weeks (W) while the median duration of response was 33.1 W. The most common grade 3 AEs were neutropenia (81%), lymphopenia (75%), and leukopenia (75%). In another phase Ib trial involving 10 pts with RRMM, ISA (10-20 mg/kg) in combination with carfilzomib (CFZ) (27 mg) was given. The median number of prior lines of therapy was 4.5 (2-8). The ORR was 80% with VGPR in 20% pts and PR in 60% pts. The most common grade 3 and 4 AEs were lymphopenia (64%), anemia (9%), and neutropenia (9%). In a phase Ib trial involving 15 pts with NDMM, ISA (10 mg) in combination with bortezomib (V) (1.3 mg/m2) and cyclophosphamide (CY) (300 mg/m2) was given. The median age of pts was 71 y (r= 68-80). The ORR was 87% with CR in 33% pts, VGPR in 27% pts, and PR in 27% pts. The median time to first response was 1.5 M while the median duration of response was 11 M. The most common grade 3 and 4 AEs were lymphopenia (50%), leucopenia (18%), neutropenia (8%), anemia (6%) and thrombocytopenia (6%). Conclusion: In RRMM pts, ISA as a single agent has shown weaker efficacy when compared to combination regimens i.e. ORR 21% vs. 58%. The best result was seen when ISA was used in combination with CFZ demonstrating an ORR of 80%. In NDMM pts, combination regimens have shown excellent efficacy with an ORR of 87%. Nausea and fatigue were the major AEs reported with the monotherapy while neutropenia, leucopenia, and lymphopenia were the major AEs reported with the combination regimens. Further studies involving a larger population are required to gather evidence in favor of the improved efficacy and to evaluate AEs. Disclosures No relevant conflicts of interest to declare.

Overcoming docetaxel resistance in advanced castration-resistant prostate cancer (CRPC): A phase I/II trial of the combination of temsirolimus and docetaxel.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 250-250 ◽  
Author(s):  
Ignacio Duran ◽  
Clara Montagut ◽  
Emiliano Calvo ◽  
Susana Galtes ◽  
Alicia Navarrete ◽  
...  
Keyword(s):  
Advanced Solid Tumors ◽  
Castration Resistant Prostate Cancer ◽  
Mechanisms Of Resistance ◽  
Docetaxel Resistance ◽  
Castration Resistant ◽  
Common Grade ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Dose Levels ◽  
Preclinical Work

250 Background: Mechanisms of resistance to docetaxel (D) are not fully understood. Preclinical work showed that administration of temsirolimus (T) between courses of D delays the growth of PTEN deficient tumors in xenografts. (Wu et al. Cancer Res 2005) The current study aims to determine the recommended phase II dose (RPTD), toxicity, pharmacokinetics (PK) and preliminary activity of D in combination with T in CRPC patients (pts). Methods: Pts aged ≥ 18 with advanced solid tumors refractory to standard therapy, ECOG ≤2, adequate bone marrow and renal function were eligible. D was given once q. 3 weeks along with T on days 2, 9 &16. The protocol was later amended and day 9 of T omitted due to excessive myelotoxicity. A 3+3 rule dose escalation was used with the next dose levels (DL) planned: DL1: D 50mg/m2, T 15 mg; DL2: D 65mg/m2, T 15 mg; DL3: D 75mg/m2, T 15 mg; DL4: D 75mg/m2, T 25 mg. An expanded cohort for pts with CRPC who have progressed to D will enroll pts once the RPTD has been defined. Results: To date 13 pts have been enrolled, median age = 65 (range 35–76), 9 male and 8 ECOG 0, Forty-seven cycles (median: 2; range: 1–9) were administered. The most frequent related adverse events (AEs) of all grades expressed as % of cycles were: leucopenia (80.8%), hyperglycemia (70.2%), anemia (68.1%) and hypercholesterolemia (65.9%). The most common Grade 3–4 AEs as % of cycles were: leucopenia (27.6%), neutropenia (29.7%), and hypophosphatemia (23%). Two pts in DL2 experienced dose limiting toxicities (DLT) consisting of intolerable grade 2 mucositis and febrile neutropenia respectively. DL1 was expanded and 3 additional pts treated with no DLTs. No drug-drug PK interactions were observed. Among 13 pts evaluable for response, 6 (2 pancreas, 2 CRPC, 1 rectal and 1 sarcoma) achieved stable disease. One pt with CRPC who had previously progressed on docetaxel received 9 cycles of treatment with sustained clinical benefit. The expanded cohort for CRPC patients is opened and recruiting. Conclusions: T and D can be safely combined at reduced doses of both agents with no PK interaction. Preliminary antitumor activity has been observed in CRPC patients. Data on the expanded cohort will be presented.

Updated analysis of the inducible T-cell co-stimulatory receptor (ICOS) agonist, GSK3359609 (GSK609), combination with pembrolizumab (PE) in patients (pts) with anti-PD-1/L1 treatment-naïve head and neck squamous cell carcinoma (HNSCC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6517-6517
Author(s):  
Eric Angevin ◽  
Stefanie L. Groenland ◽  
Annette May Ling Lim ◽  
Juan Martin-Liberal ◽  
Victor Moreno ◽  
...  
Keyword(s):  
T Cell ◽  
Single Agent ◽  
Human Study ◽  
Clinical Activity ◽  
Metastatic Setting ◽  
Anti Cancer ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Line Of Therapy ◽  
Dose Levels

6517 Background: INDUCE-1 (NCT02723955) is a first-in-human study investigating GSK609, an IgG4 ICOS agonist non-T-cell depleting antibody, as monotherapy and combination therapy with anti-cancer agents that includes PE. A range of GSK609 dose levels (≥0.1–1 mg/kg) having biological and clinical activity were identified and evaluated in the expansion phase with GSK609 0.3 mg/kg selected as the dose for further investigation. Results from the HNSCC expansion cohorts (ECs) showed GSK609 has single agent activity in pts with relapsed/refractory disease, and early clinical activity in combination with PE in pts with anti-PD-1/L1 treatment-naïve disease (Rischin, et al. Annals of Oncol 2019;30[Supplement_5]:v454–5). Updated results from the GSK609/PE HNSCC EC are presented. Methods: Eligible pts for the HNSCC EC had anti-PD-1/L1 treatment-naïve disease, ≤5 prior lines of therapy, measurable disease, and no active autoimmune disease. Pts received GSK609 0.3 mg/kg + PE 200 mg every 3 weeks (wks) until disease progression or unacceptable toxicity, up to 2 years (yrs)/35 cycles. Disease assessments were performed every 9 wks through wk 54 then every 12 wks thereafter. Pts were followed for survival and subsequent anti-cancer therapy. Results: As of 11 October 2019, 34 pts were enrolled and evaluable for efficacy analyses. The median age of this population was 61.5 yrs (range: 37–77); 85% were male; 53% received ≥1 prior line of therapy in the metastatic setting. ORR was 26% (95% CI: 12.9, 44.4; n = 9 with 4 complete and 5 partial responses); disease control rate was 68% (95% CI: 49.5, 82.6; n = 23). Among pts with PD-L1 IHC status by 22C3 pharmDx assay (n = 24; 71%), the majority of pts with a response or stable disease (SD) had PD-L1 CPS status < 20 (11 of 15 pts including 1 SD pt with CPS < 1). Median PFS was 5.6 months (95% CI: 3.9, 6,2). Median OS was not reached at time of analysis (95% CI: 8.2, NR); 6-month OS rate was 84% (95% CI: 66, 93). Treatment-related adverse events were reported in 66% of pts; the majority of events were Grades 1 or 2 with < 10% of pts experiencing ≥ Grade 3 events. Conclusions: This updated analysis with a more mature dataset shows promising clinical activity that supports further randomized investigation of GSK609 in combination with PE with an OS endpoint in HNSCC. Clinical trial information: NCT02723955 .

scholarly journals A Phase Ib/II Study of Ibrutinib in Combination with Obinutuzumab-Gazyva As First-Line Treatment for Patients with Chronic Lymphocytic Leukemia > 65 Years Old or with Coexisting Conditions

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1863-1863
Author(s):  
Juliana Velez Lujan ◽  
Michael Y. Choi ◽  
Chaja Jacobs ◽  
Colin McCarthy ◽  
Alaina Heinen ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Grade 3

Abstract Standard treatment for patients with chronic lymphocytic leukemia (CLL) is rapidly evolving and gradually has incorporated the combined use of monoclonal antibodies (mAbs) and targeted therapy with small molecules. Single agent Ibrutinib (Ibr), a first-in-class BTK inhibitor, is effective in previously untreated patients including those that are older than 65 or considered unfit to receive chemotherapy-based combinations. The complete response rate in patients receiving single agent Ibr is relatively low (overall response rate of 86% and complete response of 4% based on 2008 iwCLL criteria), though most patients have durable remissions. The combination of Ibr with mAbs like Obinutuzumab-Gazyva (G), a third-generation anti-CD20 mAb, can ameliorate the Ibr-induced lymphocytosis and increase the overall and complete response rates. Accordingly, we initiated an open-label phase Ib/II clinical study of Ibr in combination with G for first-line therapy of previous untreated pts with CLL. The study completed enrollment of 32 previously untreated patients with CLL. Patients received G administered based on FDA dosing recommendations for 6 cycles (28 days/cycle) and Ibr 420mg po (1-3 hours before starting G infusion), and daily for up to 3 years. All patients received prophylactic medications. Patients were assessed for response by 2008 iwCLL criteria two months after completion of G, as the primary efficacy endpoint. The median age of the patients was 65 (range: 46-78) years. 84% of the patients had a CIRS >6, 45% had a Rai stage III-IV and 19% had an ECOG performance ≤2. The median baseline absolute lymphocyte count (ALC) was 79x103/mm3(range: 1.4-412.4). Patients showed the following FISH/cytogenetic abnormalities: del(13q) in 55%, trisomy 12 in 23% and del(11q) in 19%. Only 2 (6%) of these patients showed del(17p). From the patients with IGVH mutational status available (n=17), 11 (65%) were unmutated (>98% homology). Most adverse events (AEs) were grade 1-2 (74%). Six patients (19%) had grade 1-2 G-infusion-related reaction (IRR) and only one patient (3%) showed grade 3 IRR (without the need for G discontinuation). We observed neutropenia (all grades: 52%, grade 3-4: 23%), thrombocytopenia (all grades: 71%, grade 3-4: 19%) and anemia (all grades: 26%). There were no cases of febrile neutropenia. Two patients (6%) had grade 1 bleeding (one patient with asymptomatic lower gastrointestinal bleeding and the second patient with epistaxis) that resolved spontaneously without requirement of blood transfusion or study treatment discontinuation. Two patients (6%) developed pneumonia, one was community-acquired pneumonia requiring inpatient treatment with IV antibiotics; the study treatment was held until resolution of symptoms and re-initiated at full dose. The most frequent non-hematological AEs were diarrhea, transaminitis, hyperbilirubinemia, hyperglycemia, and electrolyte alterations (grade 1-2). Three patients (9%) discontinued Ibr due to atrial fibrillation grade 1 (n=1), rash and headaches grade 2 (n=1), and persistent grade 4 thrombocytopenia (n=1). Twenty-three patients were evaluable for response assessment by 2008 iwCLL criteria (median follow-up of 11 months). 84% of the patients showed a rapid decrease in ALC from baseline during the first cycle of treatment and only four patients (13%) required more than 3 cycles of treatment to achieve an ALC response. The overall response rate was 100%. The majority of pts had a partial response and six of 23 evaluable patients (26%) achieved a complete remission with detectable Minimal Residual Disease in the bone marrow by multiparametric flow cytometry. In summary, Ibr-G combination has been generally well tolerated. AEs have been consistent with the known safety profiles of Ibr and G individually. The patients that discontinued Ibr remain in follow-up without disease progression. 100% of evaluable patients achieved response after 6 months of combination therapy, and 26% of patients met CR criteria. One important finding thus far has been a very low rate of IRR, (19% grade 1-2 and 3% grade 3-4), suggesting that Ibr can strongly mitigate the incidence and severity of G associated IRR. Disclosures Choi: AbbVie, Inc: Consultancy, Speakers Bureau; Rigel: Consultancy; Gilead: Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Genentech: Speakers Bureau. Amaya-Chanaga:AbbVie: Equity Ownership, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.; Pharmacyclics, an AbbVie Company: Employment, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.. Kipps:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy; Verastem: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Genentech Inc: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees. Castro:F. Hoffmann-La Roche: Consultancy; Genentech, Inc: Consultancy; Pharmacyclics, LLC, an AbbVie Company:: Consultancy.

Capecitabine and cisplatyl as neoadjuvant treatment of locally advanced nasopharyngeal carcinoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e17036-e17036
Author(s):  
E. Kerboua
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Single Agent ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Stage Iv ◽  
Complete Response ◽  
Tolerability Profile ◽  
Common Grade ◽  
Hand Foot Syndrome ◽  
Grade 3

e17036 Background: The main objective of this study is to evaluate the activity and safety of capecitabine (X) and cisplatyl (C) in patients (pts) with locally advanced nasopharyngeal carcinoma(NPC). Capecitabine was reported to have single-agent activity in advanced/metastatic NPC. Combination of X and C should provide a convenient and active regimen. Methods: Pts with undifferentiated NPC type were enrolled from July 2007 to September 2008. They received X 1,000 mg/m2orally bid on days 1–14 + C 75/m2 IV day 1 q 3W, Three cycles were administered in a neoadjuvant setting before radiotherapy. The primary endpoint was overall response rate (ORR). Results: Forty-one (41) pts have been enrolled 28 male/13 female with locally advanced NPC: 15 pts (36,6% ) were stage III (UICC 1997) 26 pts (63,3%) stage IV (n = 6 IVA and n = 20 IVB). All pts were evaluated for safety and 36 pts for response. ORR was 86% with 63,8% (n = 23) complete response (CR), 22,2% (n = 8) partial response (PR), 2 progression disease (PD) and 2 stable disease (SD). The most common grade 3/4 adverse events were diarrhea 4,8% (n = 2), neutropenia 7,3% (n = 3), thrombocytopenia 7,3% (n = 3), vomiting 9,7% (n = 4) . Two pts died from sepsis that was probably treatment-related. A hand-foot syndrome was observed in 25% of pts (grade 1/2). Conclusions: Preliminary results show that X plus C provide an active regimen with an acceptable tolerability profile as neoadjuvant chemotherapy for locally advanced NPC. This regimen requires a shorter hospital stay and is more convenient for pts compared with the gold standard 5-FU plus cisplatyl. No significant financial relationships to disclose.

scholarly journals Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience

Blood ◽  
2018 ◽  
Vol 131 (17) ◽  
pp. 1910-1919 ◽  
Author(s):  
Susan O’Brien ◽  
Richard R. Furman ◽  
Steven Coutre ◽  
Ian W. Flinn ◽  
Jan A. Burger ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Single Agent ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Key Points ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Over Time ◽  
Safety Signals

Key Points Our 5-year experience shows sustained single-agent efficacy of ibrutinib in CLL patients, with complete response rates increasing over time. Long-term ibrutinib was well tolerated with no new safety signals; rates of grade ≥3 cytopenias decreased with continued therapy.

scholarly journals EPCT-17. A PHASE I AND SURGICAL STUDY OF RIBOCICLIB AND EVEROLIMUS IN CHILDREN WITH RECURRENT OR REFRACTORY MALIGNANT BRAIN TUMORS: PEDIATRIC BRAIN TUMOR CONSORTIUM INTERIM REPORT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii307-iii307
Author(s):  
Mariko DeWire ◽  
Christine Fuller ◽  
Olivia Campagne ◽  
Tong Lin ◽  
Haitao Pan ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Single Agent ◽  
Pediatric Brain Tumor ◽  
Pi3k Pathway ◽  
Neurosurgical Procedures ◽  
Common Grade ◽  
Grade 3

Abstract Genomic aberrations in the cell cycle and PI3K pathway are commonly observed in recurrent childhood brain tumors. Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dosage (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus was determined in the Phase I study and ribociclib concentrations were characterized in plasma and tumor in children undergoing neurosurgical procedures. Following resection, eligible patients were enrolled in the Phase I study according to a rolling 6 design and received ribociclib and everolimus once daily for 21 days and 28 days, respectively. Patients undergoing surgery received ribociclib at the pediatric RP2D (350 mg/m2/day) for 7–10 days pre-operatively. Pharmacokinetic samples were collected on both cohorts and analyzed in nine patients on phase I study. Sixteen eligible patients enrolled on phase I study (median age 10.3 years; range: 3.9–20.4) and 5 patients were enrolled on the surgical cohort (median age 11.4 years; range: 7.2–17.1). Six patients enrolled at dose level 1 without dose limiting toxicities (DLT). Two of the three patients at dose level 2 experienced DLT (grade 3 hypertension and grade 4 ALT). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leucopenia. Everolimus concentrations following administration of everolimus alone were lower than those following drug combination, suggesting an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus in recurrent CNS tumors is 120 mg/m2 and 1.2 mg/ m2 daily for 21 days and 28 days, respectively.

Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma

Blood ◽  
2009 ◽  
Vol 114 (4) ◽  
pp. 772-778 ◽  
Author(s):  
Paul Richardson ◽  
Sundar Jagannath ◽  
Mohamad Hussein ◽  
James Berenson ◽  
Seema Singhal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Agent ◽  
Progression Free Survival ◽  
Prior Treatment ◽  
Once Daily ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Treatment Regimens ◽  
Common Grade ◽  
Grade 3

Abstract Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed and refractory MM. Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance. Response, progression-free survival (PFS), overall survival (OS), time to progression (TTP), and safety were assessed. Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (60%), thrombocytopenia (39%), and anemia (20%), which proved manageable with dose reduction. Grade 3 or 4 febrile neutropenia occurred in 4% of patients. Lenalidomide monotherapy is active in relapsed and refractory MM with acceptable toxicities. These data support treatment with single-agent lenalidomide, as well as its use in steroid-sparing combination approaches. The study is registered at http://www.clinicaltrials.gov as NCT00065351.

GEIS 39: Phase II trial of nabpaclitaxel for the treatment of patient with multiply relapsed/refractory desmoplastic small round cell tumor (DSRCT) and Ewing sarcoma (EwS).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11529-11529
Author(s):  
Jaume Mora ◽  
Mariona Suñol ◽  
Nadia Hindi ◽  
Alicia Castañeda ◽  
Andrés Redondo ◽  
...  
Keyword(s):  
Single Agent ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Free Survival ◽  
Pediatric Solid Tumors ◽  
Meaningful Activity ◽  
Common Grade ◽  
Central Pathology ◽  
Grade 3 ◽  
Further Development

11529 Background: Nab-paclitaxel (albumin-bound paclitaxel) has shown preclinical activity against pediatric solid tumors. Preclinical data in EwS PDX models suggested high activity of nab-paclitaxel in tumors expressing high-levels of SPARC. Tumoral SPARC facilitates the accumulation of albumin in the tumor and increases the effectiveness of albumin-bound paclitaxel. Nab-paclitaxel utilizes albumin to deliver paclitaxel via caveolin-mediated endocytosis which is expressed in the EwS cells surface. We hypothesized that SPARC can be a predictive biomarker for nab-paclitaxel in EwS and DSRCT that could potentially be relevant for a better design of clinical trials and personalized treatments using nab-paclitaxel. Methods: Main endpoint of GEIS-39 was the overall response rate (ORR) assessed by RECIST 1.1 criteria with centralized pathology and imaging review. Secondary objectives included safety according to the CTCAE 4.0 criteria. Patients aged ≥ 6 months and ≤ 40 years, with relapsed/refractory DSRCT were eligible after having received at least one previous poly-chemotherapy line; EwS must have received at least two standard chemotherapy lines. Prior taxane therapy was accepted. Central pathology review selected for tumors with > Grade 3 (intense and diffuse) expression of SPARC by immunohistochemistry to be eligible. Nab-paclitaxel was administered as follows: age ≥ 21 and ≤ 40 years: 125 mg/m2 days 1, 8 and 15 in cycles of 28 days; age ≥ 6 months and ≤ 20 years: 240 mg/m2 days 1, 8 and 15 in cycles of 28 days. A 30% ORR was anticipated with a sample size of 25 patients needed to test the hypothesis. Stopping rule was set at 1 response within the first 16 treated pts. If 5 or more successes were observed in 25 pts, the results of the trial will warrant further investigation. Results: Twenty-nine patients were enrolled from June 2017 until October 2019, 11 DSRCT and 18 EwS. Median age was 32 years (range 14-69), and 5 females and 24 males were included, having received a median of 3 previous systemic treatment lines. Patients received a median of 3 cycles of nab-paclitaxel (range 1-17). In the EwS cohort an ORR of 33.3% (all partial responses, median duration 2 months) and 16.7% of stabilizations were achieved. No objective responses were observed among DSRCT pts, but 27.3% of pts achieved a stabilization. Overall, median progression free survival was 2.8 months and median overall survival 12.1 months, with no significant differences between DSRCT and EwS cohorts. Most common grade 3 toxicities were neutropenia (20.7%) and diarrhea (10.3%). Conclusions: Single agent nab-paclitaxel in biomarker selected EwS patients, but not in DSRCT, provided clinically meaningful activity that deserves further development. Nab-paclitaxel had a manageable adverse event profile. Clinical trial information: 2016-002464-14.

Biweekly Raltitrexed in Combination with Irinotecan (RIR) as Second-Line Therapy for Patients with Metastatic Colorectal Cancer: A Non-Randomized, Open-Label Phase II Trial.

2020 ◽  
Author(s):  
Ke Cheng ◽  
Yu-Wen Zhou ◽  
Ye Chen ◽  
Zhi-Ping Li ◽  
Meng Qiu ◽  
...  
Keyword(s):  
Adverse Events ◽  
Overall Response Rate ◽  
Progression Free Survival ◽  
Second Line ◽  
Open Label ◽  
Second Line Therapy ◽  
Free Survival ◽  
Common Grade ◽  
Open Label Phase ◽  
Grade 3

Abstract Background Irinotecan-based doublet chemotherapy strategy was standard second-line backbone treatment for patients with oxaliplatin‑refractory metastatic colorectal cancer(mCRC). The aim of this study was to evaluate tolerability and efficacy of raltitrexed combined with irinotecan biweekly administered as the second-line therapy for mCRC patients.Methods The study was a single-center, non-randomized, open-label phase II trial. Patients with mCRC after failure with first-line treatment of oxaliplatin and fluoropyrimidine or its derivatives were enrolled. Irinotecan (180 mg/m2) and raltitrexed (2.5 mg/m2) were given intravenously on day 1. Cycles were repeated every 2 weeks. The primary endpoint was progression-free survival, and the secondary endpoints included overall response rate, disease control rate, overall survival and treatment related adverse events. Results Between December 2012 and October 2016, 35 patients were enrolled. 33 and 35 patients were assessed for response and safety, respectively. The overall response rate (ORR) was 8.6 %, and the disease control rate (DCR) was 71.4%. The median progression-free survival (PFS) was 4.5 months (95% CI 3.8–5.2). The median overall survival was 12.0 months (95% CI 8.5–15.5). Four patients received conversion therapy to no evidence of disease (NED), and 2 patients were still alive with beyond 24 months survival. The most common grade 3/4 hematological adverse events were leukopenia (8.6%), neutropenia (5.7%). The most common grade 3/4 nonhematological adverse events were anorexia (14.3%), vomiting (14.3%), nausea (11.4%) and fatigue (8.6%). Two patients discontinued the protocol treatment because of treatment-related gastrointestinal adverse events. No one died from treatment-related events. The incidence and severity of toxicity was irrelevant to UGT1A1 status.Conclusions The combination of irinotecan with raltitrexed is an active, convenient and acceptable toxic regimen for second-line treatment for mCRC patients, which needs further study as a chemotherapy backbone to be combined with targeted agents in mCRC.Trial registration No. ChiCTR-ONC-12002767. The study was registered with the Chinese Clinical Trial Registry at 29 Octorber 2012, http://www.chictr.org.cn/index.aspx.

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