Phase Ib/II study of eribulin mesylate administered in combination with gemcitabine/cisplatin as first-line therapy for locally advanced or metastatic bladder cancer: Phase Ib results.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 273-273 ◽  
Author(s):  
Nicholas J. Vogelzang ◽  
Paul Conkling ◽  
Ignacio Duran ◽  
José Pablo Maroto ◽  
Manuel Modiano ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Standard Dose ◽  
Locally Advanced ◽  
Clinical Activity ◽  
Limiting Factor ◽  
Hematologic Toxicity ◽  
Synthetic Analog ◽  
Eribulin Mesylate ◽  
Phase Ib ◽  
Overall Response

273 Background: Eribulin mesylate (E) is a synthetic analog of the natural, marine-sponge product halichondrin B. A phase (Ph) II study of E monotherapy in urothelial carcinoma with no prior cytotoxic therapy for advanced disease reported an overall response rate of 38% (95% CI: 23%, 54%; Quinn et al ASCO 2010, abstract 4539). Therefore, we combined E with gemcitabine (G) and cisplatin (C) to assess the feasibility, safety, and preliminary activity of the combination, in patients (pts) with advanced bladder cancer. This is an open-label, multicenter study consisting of a Ph Ib and Ph II portion. Methods: In the Ph Ib portion, three ascending doses of E were to be administered IV on days 1 and 8 q21d to determine the MTD with standard doses of G (1000 mg/m2, days 1 and 8 q21d) and C (70 mg/m2, day 1). In Ph II, pts are randomized 1:1 to E plus G/C, or G/C alone. Results: Nine pts (median age: 59 years; 7 male/2 female) entered Ph Ib. Pts received E 0.7 mg/m2 (n=3) or 1.0 mg/m2 (n=6), with standard dose G/C. Thirty-four cycles were given (2 pts are ongoing). One dose-limiting toxicity (DLT) was observed at 1.0 mg/m2 (Gr 4 thrombocytopenia). The 1.4 mg/m2 dose of E was not explored due to an investigator consensus that, with that dose, the probability of DLTs (severe hematologic toxicity) developing was high. Thus, the MTD was not achieved or defined. The recommended Ph II dose (RP2D) of E in combination with G/C was established as 1.0 mg/m2. Most common adverse events at the RP2D were nausea (83%), neutropenia (83%), fatigue (83%), thrombocytopenia (83%), anemia (83%), and anorexia (50%). Best responses at 1.0 mg/m2 were 1 complete response (CR) (unconfirmed) and 4 partial responses (PR) (all confirmed). Overall response for both cohorts was 89% – 2 CRs (1 confirmed, 1 unconfirmed) and 6 PRs (4 confirmed, 2 unconfirmed). Six pts have been randomized into the Ph II portion of the study to date. Conclusions: E combined with standard G/C chemotherapy is feasible and has encouraging clinical activity. Hematologic toxicity is the main limiting factor.

ABC-08: A phase Ib, multi-centre, open-label study of a first-in-class nucleotide analogue NUC-1031 in combination with cisplatin in patients with locally advanced/metastatic biliary tract cancers.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS544-TPS544 ◽  
Author(s):  
Mairead Geraldine McNamara ◽  
John A. Bridgewater ◽  
Daniel H. Palmer ◽  
Harpreet Singh Wasan ◽  
David Ryder ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Standard Dose ◽  
Performance Status ◽  
Locally Advanced ◽  
Clinical Activity ◽  
Cancer Resistance ◽  
Open Label ◽  
Ecog Performance Status ◽  
Biliary Tract Cancers ◽  
Phase Ib

TPS544 Background: The UK ABC-02 study established cisplatin and gemcitabine as the reference regimen for first-line treatment of patients (pts) with advanced biliary tract cancers (BTCs) (median overall survival (OS): 11.7 months). No clinical studies since ABC-02 have reported an extension in OS, and therefore effective new agents/combinations are required. NUC-1031 was designed to improve on gemcitabine’s relatively poor efficacy by overcoming its associated key cancer resistance mechanisms, through cellular uptake independent of nucleoside transporters, activation independent of deoxycytidine kinase and protection from cytidine deaminase inactivation, resulting in over 200x the intracellular levels of the anti-cancer metabolite, dFdCTP, greater stability and reduction in the generation of toxic metabolites. NUC-1031 showed activity as monotherapy in a phase I/II study in 7 pts with BTC, refractory to all standard treatments (Blagden et al ASCO 2015; abstract 2514). Methods: ABC-08 is a multi-centre phase Ib study of NUC-1031 combined with cisplatin in pts with non-resectable or recurrent/metastatic cholangiocarcinoma, gallbladder or ampullary carcinoma, aged ≥18 years with an ECOG performance status of 0-1, who have received no prior systemic therapy. The starting dose for NUC-1031 is 625 mg/m2 administered IV on days 1 and 8 in combination with cisplatin (standard dose of 25 mg/m2) (21 day schedule). The dose will be escalated sequentially in cohorts of 3-6 pts using an accelerated titration procedure (725mg/m2, 825mg/m2, 925mg/m2). Treatment will continue until intolerable toxicity/progressive disease. The primary endpoints are safety and RP2D. Secondary endpoints are progression-free survival, OS, response rate and pharmacokinetic endpoints, including assessments of multiple plasma and intracellular analytes: NUC-1031, cisplatin, dFdC, dFdCMP, dFdCDP, dFdCTP and dFdU, and will be correlated with safety profile and clinical activity. Planned accrual is 15-24 pts over 2 years. Cohort 1 has been completed without dose-limiting toxicities. Enrolment to cohort 2 is on-going. Clinical trial information: NCT02351765.

A phase II, randomized study of nivolumab (nivo) or nivo plus BMS-986205 with or without intravesical Bacillus Calmette-Guerin (BCG) in BCG-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC): CheckMate 9UT.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS493-TPS493 ◽  
Author(s):  
Noah M. Hahn ◽  
Sam S. Chang ◽  
Maxwell Meng ◽  
Neal D. Shore ◽  
Badrinath R. Konety ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Locally Advanced ◽  
Unmet Need ◽  
Clinical Activity ◽  
Free Survival ◽  
Bcg Therapy ◽  
Intravesical Bcg

TPS493 Background: Immune checkpoint inhibitors, including nivo (anti–PD-1), have demonstrated favorable tolerability and efficacy profiles, ushering in a new treatment (tx) paradigm for advanced bladder cancer (advBC). However, an unmet need exists for new effective tx options in earlier stages of disease, specifically for patients (pts) with BCG-unresponsive, high-risk NMIBC. Increased IDO and PD-L1 expression in NMIBC tumors (Inman, et al. Cancer 2007; Hudolin, et al. Anticancer Res 2017), support the combination of anti–PD-1 and IDO1 inhibition in NMIBC. BMS-986205, a selective, potent, once-daily IDO1 inhibitor that works early in the IDO1 pathway, has demonstrated clinical activity in combination with nivo in pts with immunotherapy-naive advBC who received ≥ 1 prior line of therapy (objective response rate, 37%; Tabernero, et al. J Clin Oncol 2018;36(suppl) [abstr 4512]). These findings provide a rationale for investigation of nivo + BMS-986205 ± intravesical BCG therapy in BCG-unresponsive high-risk NMIBC. Here we describe a phase 2, randomized, open-label study assessing the safety and efficacy of nivo ± BMS-986205 ± intravesical BCG in pts with BCG-unresponsive, high-risk NMIBC. Methods: Pts aged ≥ 18 years with BCG-unresponsive (per February 2018 FDA guidance), high-risk NMIBC, defined as carcinoma-in-situ (CIS) with or without papillary component, any T1, or Ta high-grade lesions, will be enrolled. Pts must have urothelial carcinoma as the predominant histological component (>50%). Key exclusion criteria include locally advanced or metastatic BC, upper urinary tract disease within 2 years, prostatic urethral disease within 1 year, and prior immunotherapy. Using a novel adaptive-type design, pts will be randomized to 1 of 4 tx arms with nivo ± BMS-986205 ± BCG. Primary endpoints include proportion of pts with CIS with complete response (CR), duration of CR in pts with CIS, and event-free survival for all pts without CIS. Secondary endpoints are progression-free survival and safety. This global study in 13 countries is underway, with a target enrollment of 436 pts. ( Clinical trial information: NCT03519256.

Phase Ib study to assess the safety, tolerability, and clinical activity of gedatolisib in combination with palbociclib and either letrozole or fulvestrant in women with metastatic or locally advanced/recurrent breast cancer (B2151009; NCT02684032).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS1113-TPS1113 ◽  
Author(s):  
Andres Forero-Torres ◽  
Robert Wesolowski ◽  
Aditya Bardia ◽  
Haresh S. Jhangiani ◽  
Peter Kabos ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Therapy ◽  
Primary Endpoint ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Mtor Pathway ◽  
Clinical Activity ◽  
Phase Ib ◽  
Metastatic Setting

TPS1113 Background: Hormone receptor positive (HR+) disease is the most common subset of both early and late stage breast cancer (BC). The majority of women with HR+ metastatic BC (MBC) ultimately develop resistance to endocrine therapy, with a median survival of ~2-3 years. A new standard-of-care strategy to treat HR+ metastatic disease involves the combination of hormone therapy and cyclin-dependent kinase (CDK) 4/6 inhibition, which has demonstrated improved progression-free survival (PFS) in both the first- and later-line metastatic setting. More recently, preclinical data with the dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor gedatolisib (PF-05212384) suggest synergy with the combination of hormone therapy, CDK 4/6 inhibition, and inhibition of the PI3K/mTOR pathway. Methods: This phase Ib study includes a dose escalation portion to evaluate dose-limiting toxicities (primary endpoint) and determine the recommended phase II dose for triplet therapy with gedatolisib combined with palbociclib/letrozole or palbociclib/fulvestrant in women with HR+ HER2-negative MBC or locally advanced/recurrent BC, in the first- and later-line setting. Thereafter, a 3-arm expansion for early signals of efficacy will investigate objective response rates (primary endpoint) with gedatolisib combined with palbociclib/letrozole (n = 26), palbociclib/fulvestrant in patients without prior CDK 4/6 inhibition (n = 28), and palbociclib/fulvestrant in patients who have previously received palbociclib (n = 27). The rates of objective response will be compared to historical controls. Secondary endpoints include safety, tumor response, PFS (expansion portion only), pharmacokinetics, and biomarker correlations associated with the PI3K/mTOR pathway. This trial is now recruiting. Clinical trial information: NCT02684032.

Clinical Activity of Azacitidine In Combination with the Oral mTOR Inhibitor Everolimus (RAD001) In Relapsed and Refractory AML: Interim Analysis of a Phase Ib/II Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3301-3301
Author(s):  
Andrew H Wei ◽  
Sonali Sadawarte ◽  
John Catalano ◽  
Anthony P. Schwarer ◽  
Sharon Avery ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Overall Response Rate ◽  
Mtor Inhibitor ◽  
Response Rate ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Phase Ib ◽  
Overall Response ◽  
Refractory Aml

Abstract Abstract 3301 Background Although the demethylating agent azacitidine has an established role in myelodysplastic syndromes and encouraging activity in oligoblastic acute myeloid leukemia (AML), information regarding its role in relapsed and refractory AML is still emerging. The French ATU reported an overall response rate (ORR; CR/CRi+PR) in relapsed and refractory AML of 11% (Itzykson et al. ASH 2009 #1054). In a similar population, azacitidine salvage therapy produced a CR/CRi rate of 19% (Ayari S, et al. ASH 2009 #2044). Rapamycin, an inhibitor of the AKT downstream target mammalian Target Of Rapamycin (mTOR), is reported to specifically target leukemic stem cells and orally bioavailable rapamycin derivatives, such as everolimus (RAD001), are in active clinical development. Clinical responses with single agent everolimus in relapsed, refractory AML, however, have been modest (Yee et al, Clin Cancer Research 2006 and Boehm et al, European Journal of Internal Medicine 2009). Aim Building on our experience combining everolimus with low dose cytarabine (submitted to ASH, 2010), we have sought to investigate the feasibility and preliminary efficacy of combining everolimus with azacitidine in relapsed and refractory AML. Methods Phase Ib/II open label dose escalation study. Patients were treated with azacitidine 75 mg/m2 s.c. daily on days 1–5 and 8–9 of each 28-day cycle with either 2.5, 5 or 10 mg everolimus orally on days 5–21 for a maximum of 12 cycles. Results This preliminary analysis includes 20 patients (M 14, F 6), median age 64 years (range 17–76) receiving 2.5 mg (n=6), 5 mg (n=12) or 10 mg (n=2) everolimus. 9 (45%) had chemotherapy refractory and 11 (55%) relapsed AML after 1 (n=8), 2 (n=10) or 3 (n=2) previous lines of therapy. 7/17 (41%) had poor risk and 10/17 (59%) intermediate risk cytogenetics. 6/19 (32%) had secondary AML. The overall response rate (ORR) in 14 evaluable patients was 36% (2 CR, 3 PR). Stable disease (SD) was observed in 7 (50%) patients and 2 (14%) had progressive disease. Absolute bone marrow blast reductions from baseline in the 5 responders ranged from 9 to 88% (Figure 1). Grade 3/4 non-hematologic toxicities are summarized as follows: 2.5 mg everolimus cohort- septicemia (n=1) and mucositis (n=1, dose limiting toxicity; DLT), 5 mg everolimus cohort- septic arthritis (n=1, DLT). Febrile neutropenia during the first cycle of therapy was reported in 5/20 (25%). Safety analysis in the 10 mg everolimus cohort is ongoing. With a median follow up of 82 days, 30 day mortality was 0%. Enrolment continues to a planned 40 patients. Of interest, 2 out of 3 patients with FLT3-ITD+ AML refractory to high-dose cytarabine and antracyclines, had a striking reduction in bone marrow blasts after commencing azacitidine + everolimus (2.5 mg) therapy, with the absolute blast count falling from 95% to 16% and 92% to 5%, respectively, and lasting for at least 5 months in both. One of these patients has so far proceeded to allogeneic stem cell transplant (allo-SCT). Another patient with 3rd relapse of AML after failing allo-SCT, achieved CR after 3 cycles of treatment with azacitidine + everolimus (2.5 mg) and remains in CR after 157 days. Conclusion In relapsed and refractory AML, azacitidine in combination with the mTOR inhibitor everolimus was well tolerated and demonstrates substantial clinical activity in this advanced AML population. Further evaluation of this promising combination is ongoing. Disclosures: Wei: Novartis: Advisory board, Research Funding; Celgene: Research Funding. Off Label Use: AML therapy. Catalano:Celgene: Research Funding; Roche: Honoraria, Research Funding, Travel Grants.

A phase IB study of erlotinib in combination with gemcitabine and nab-paclitaxel in patients with previously untreated advanced pancreatic cancer: An Academic GI Cancer Consortium (AGICC) study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4052-4052
Author(s):  
Lawrence P. Leichman ◽  
Bert H. O'Neil ◽  
Jordan Berlin ◽  
Colin D. Weekes ◽  
Patricia Ames ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Single Agent ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Phase Ib ◽  
Entire Cohort ◽  
Best Response ◽  
Ecog Ps

4052 Background: The combination of gemcitabine (gem) and nab-paclitaxel (nab) has demonstrated promising activity in advanced pancreatic cancer. Erlotinib (erl) adds modest benefit to gemcitabine. We initiated this phase IB study to evaluate the safety of the three drug combination and obtain preliminary evidence of efficacy. Methods: Patients (pts) with previously untreated locally advanced (la) or metastatic (met) pancreatic cancer with ECOG PS 0-1 were treated with gem and nab IV days 1,8,15 and once daily erl days 1-28 Q28 days. Standard 3+3 design was used with dose levels (DL) (gem,nab,erl): 1(1,000, 125, 100), -1 (1,000, 100, 100), -2 (1,000, 75, 100), -3 (1,000,75,75). CT scans were obtained Q 2 cycles. DLT was defined as ≥grade (gr) 3 non-hematologic, febrile neutropenia, ≥gr 3 thrombocytopenia, or missing ≥2 doses gem, nab or >5 doses erl within first cycle (C). Results: Nineteen pts were enrolled and completed a total of 62 cycles (range 0-11). Pt characteristics: M/F (9/10), White/Hispanic/AA (15/2/2), median age 63 (range 54-78), ECOG PS 1=11, met/la (12/7). In DL1, 1/3 pts had gr3 dehydration in C 2 and 1/3 had gr 4 neutropenia/sepsis in C 4. Although not formally DLT, 3 more pts were enrolled. Of the next 3 pts, 1 DLT of gr 3 diarrhea/gr 4 neutropenia in C 1 was noted and 1 other pt DC’d therapy for neutropenia after 2 cycles. Of 3 pts in DL -1, 2 DLTs (gr 3 optic neuropathy, too many missed doses) were observed. Of 3 pts in DL -2, 2/3 had DLT (gr 3 esophagitis/fatigue and gr 3 transaminitis). Of 6 evaluable pts in DL -3, no DLTs were observed. Most common gr 3/4 toxicities were neutropenia (9), dehydration, thrombocytopenia (3 each), and hypotension (2). Of 13 pts evaluable for response, 6 had partial response (46%), 5 stable disease (38%), and 2 progressive disease (15%) as best response. Median PFS and OS of entire cohort were 5.3 and 9.3 months respectively. Conclusions: The combination of erlotinib with gemcitabine and nab-paclitaxel is not tolerable at standard single agent dosing of all drugs. However, significant clinical activity was noted, even at DL -3. Further study of the combination will need to incorporate reduced dosing.

A phase II, randomized study of nivolumab (NIVO), NIVO plus linrodostat mesylate, or NIVO plus intravesical bacillus Calmette-Guerin (BCG) in BCG-unresponsive, high-risk, nonmuscle invasive bladder cancer (NMIBC): CheckMate 9UT.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5090-TPS5090
Author(s):  
Noah M. Hahn ◽  
Sam Chang ◽  
Maxwell Meng ◽  
Neal D. Shore ◽  
Badrinath R. Konety ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Checkpoint Inhibitors ◽  
Randomized Study ◽  
Objective Response ◽  
Locally Advanced ◽  
Unmet Need ◽  
Clinical Activity ◽  
Bcg Therapy ◽  
Intravesical Bcg

TPS5090 Background: Immune checkpoint inhibitors, including NIVO (anti–PD-1), have demonstrated favorable tolerability and efficacy profiles, ushering in a new treatment (tx) paradigm for advanced bladder cancer (advBC). However, an unmet need exists for new effective tx options in earlier stages of disease, specifically for patients (pts) with BCG-unresponsive, high-risk NMIBC. Increased IDO and PD-L1 expression in NMIBC tumors (Inman, et al. Cancer 2007; Hudolin, et al. Anticancer Res 2017), support the combination of anti–PD-1 and IDO1 inhibition in NMIBC. Linrodostat mesylate, a selective, potent, once-daily IDO1 inhibitor, has demonstrated clinical activity in combination with NIVO in pts with immunotherapy-naive advBC who received ≥ 1 prior line of therapy (objective response rate, 37%; Tabernero, et al. J Clin Oncol 2018;36(suppl) [abstr 4512]). Furthermore, high levels of PD-L1 expression have been reported in patients not responding to BCG tx. These findings provide a rationale for investigation of NIVO ± linrodostat ± intravesical BCG therapy in BCG-unresponsive high-risk NMIBC. Here we describe a phase 2, randomized, open-label study assessing the safety and efficacy of NIVO ± linrodostat ± intravesical BCG in pts with BCG-unresponsive, high-risk NMIBC (NCT03519256). Methods: Pts aged ≥ 18 years with BCG-unresponsive (per February 2018 FDA guidance), high-risk NMIBC, defined as carcinoma-in-situ (CIS) with or without papillary component, any T1, or Ta high-grade lesions, will be enrolled. Pts must have urothelial carcinoma as the predominant histological component ( > 50%). Key exclusion criteria include locally advanced or metastatic BC, upper urinary tract disease within 2 years, prostatic urethral disease within 1 year, and prior immunotherapy. Using a novel adaptive-type design, pts will be randomized to 1 of 4 tx arms with NIVO ± linrodostat ± BCG. Primary endpoints include proportion of pts with CIS with complete response (CR) and duration of CR in pts with CIS. Secondary endpoints are progression-free survival and safety. This global study in 14 countries is underway, with a target enrollment of 436 pts. Clinical trial information: NCT03519256 .

scholarly journals Eribulin plus trastuzumab in pretreated HER2-positive advanced breast cancer patients: safety and efficacy. An Italian experience

2019 ◽  
Vol 106 (4) ◽  
pp. 301-305
Author(s):  
Eufemia S. Lutrino ◽  
Laura Orlando ◽  
Antonio Febbraro ◽  
Marianna Giampaglia ◽  
Claudio Zamagni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Standard Dose ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Median Number ◽  
Clinical Activity ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Eribulin Mesylate ◽  
Italian Experience

Background: Chemotherapy plus targeted therapy is the established treatment for human epidermal growth factor receptor 2 (HER2)–overexpressing breast cancer (BC). Limited data regarding the safety and activity of the combination of eribulin and trastuzumab (E/T) in pretreated HER2-positive advanced BC (ABC) are available. The aim of this observational, retrospective, multicenter study was to examine the tolerability and the clinical activity of E/T in this setting. Methods: Patients treated with eribulin mesylate plus standard dose of trastuzumab were included. Data on overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were reported. Results: Between October 2012 and November 2015, 24 consecutive patients with HER2-positive ABC were included. All patients were heavily pretreated: the median number of prior chemotherapy regimens for ABC was 3 (range 2–9). The median number of cycles with E/T was 11.5 (range 2–26). The ORR was 41.7%. Median PFS was 5.4 months, median postprogression survival was 5.4 months, and median OS was 8 months. Neutropenia was the most common grade 3/4 clinical adverse event (16.7%). Conclusions: Tolerability and clinical activity of the E/T combination schedule are encouraging. The results of this study indicate that this combination might be considered for treatment of pretreated HER2 ABC.

Phase Ib Study Of Combination Epigenetic Therapy With 5-Azacitidine and Vorinostat In Patients With Relapsed Or Refractory DLBCL

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4339-4339
Author(s):  
Tiffany Tang ◽  
Peter Martin ◽  
Rebecca L. Elstrom ◽  
Jia Ruan ◽  
Richard R. Furman ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Objective Response ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Advisory Committees ◽  
Phase Ib ◽  
Grade 3 ◽  
Experienced Grade

Abstract Introduction Patients with chemorefractory DLBCL have a poor prognosis, rarely achieving durable responses to additional treatment with standard chemotherapy. Epigenetic dysregulation likely contributes to lymphomagenesis and chemoresistance. Distinct epigenetic signatures predicted response to the DNA methyltransferase inhibitor (MTI) azacitidine (Aza) and vorinostat (V), a histone deacytelase inhibitor (HDACi) in DLBCL cell lines. Preclinical studies suggested synergy between MTI and HDACi in chemoresistant DLBCL cell lines. We performed a phase Ib trial to evaluate the combination of Aza plus V in patients with relapsed or refractory DLBCL. Methods Subjects with relapsed or refractory DLBCL ineligible for (due to chemorefractory state or comorbidities) or relapsed after autologous stem cell transplant were treated with Aza and V at four different dose levels (DL). DL 1 consisted of Aza 55mg SC x 5 days plus V 300mg PO x 7 days. DL 2 consisted of Aza 75mg SC x 5 days plus V 200mg PO x 7 days. DL 3 and 4 used the same Aza doses as DL1 and 2 respectively but V was administered for 14 days. Treatment was administered on 28-day cycles. Subjects remained on treatment for a maximum of 6 cycles. Up to 8 subjects could be enrolled into each DL, depending on the toxicity and activity profile. If 2 patients developed dose-limiting toxicities (DLT), enrolment to that dose level was closed. Cycle 1 DLT was defined as any of the following treatment-related adverse events: Grade 3-4 non-hematologic toxicity excluding alopecia, nausea, or fatigue responding to maximal treatment; grade 4 neutropenia lasting longer than 7 days or failing to recover to > 1000 cells/mm3 within 14 days; grade 4 thrombocytopenia of any duration; grade 4 febrile neutropenia. Primary endpoints were safety and tolerability as well as overall response rates (ORR). Results A total of 18 patients were enrolled. The median age was 66 years old (range 26-82). Subjects had received a median of 3 prior lines of treatment, including 3 that had undergone autologous stem cell transplantation. Thirteen patients were refractory to their previous treatment. Eight subjects were treated at DL1, 5 at DL2, 4 at DL3 and 1 at DL4. DL2 was closed early due to limited efficacy demonstrated with the 7-day course of V; only 1 out of 13 patients treated at DL1 and DL2 achieved an objective response. DL3 and DL4 were closed early after 2 patients at DL3 required dose reductions. The following grade 1-2 non-hematologic toxicities, independent of relation to study drugs, were experienced by at least 2 subjects: nausea (11), diarrhea (8), hypoglycemia (7), vomiting (5), renal impairment (5), raised ALP (5), fatigue (4), hyperglycemia (4), fever (3) and hyperbilirubinemia (3). One patient experienced grade 3 thromboembolism (DL1), 1 experienced grade 3 diarrhea (DL2), and 1 experienced grade 4 ALP increase (DL4). Grade 3-4 hematologic toxicity included thrombocytopenia (8), anemia (3) and neutropenia (2). A median of 2 cycles of study regimen was administered (range 1-6). One patient completed 6 cycles of treatment and 17 patients stopped treatment due to PD. There was 1 DLT at DL1. Only one subject had an objective response (PR at DL2) and 3 subjects had stable disease. The trial was stopped prematurely because of low clinical activity and poor tolerability. Interestingly, 7 patients (2 with relapsed disease and 5 with disease refractory to prior pre-study therapy) received treatment post-study. Retrospective review of these cases demonstrated that 2 had CR (PEP-C and R-DICE) and 3 others appeared to have had a significant clinical response (bendamustine, radioimmunotherapy, and brentuximab vedotin-PEP-C), 1 had PD (PEP-C), and 1 was not formally evaluated (bendamustine). The median OS of these 7 patients was 501 days following Aza-V. Conclusions The combination of Aza and V was poorly tolerated and had minimal clinical activity at the doses/schedules tested in this study of refractory DLBCL patients. However, we observed that several heavily pre-treated and refractory patients appeared to go on to achieve better than expected responses to the next treatment following the study regimen, perhaps consistent with a chemosensitization effect (i.e., epigenetic priming) of Aza and V. Epigenetic priming in DLBCL warrants further investigation in less refractory patients and in combination with other agents. Epigenetic profiling of patient samples derived from this trial is ongoing. Disclosures: Martin: Teva: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Speakers Bureau; Millennium: Research Funding; Seattle Genetics: Consultancy, Speakers Bureau. Ruan:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Seattle Genetics, Inc.: Membership on an entity’s Board of Directors or advisory committees. Furman:Celgene: Research Funding.

A phase Ib, open-label, dose-escalation study of tivozanib and FOLFOX6 in patients (pts) with advanced gastrointestinal (GI) tumors.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 549-549 ◽  
Author(s):  
F. Eskens ◽  
C. N. Oldenhuis ◽  
P. Bhargava ◽  
W. Loos ◽  
B. Esteves ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Kinase Inhibitor ◽  
Standard Dose ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Open Label ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Embolism And Thrombosis ◽  
Grade 3

549 Background: Tivozanib (AV-951), a highly potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, has shown additive antitumor activity with fluorouracil (5-FU) in preclinical studies. An open-label phase Ib study was conducted to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK), and antitumor activity of escalating doses of tivozanib combined with standard-dose FOLFOX6 (i.e., oxaliplatin, leucovorin, and 5-FU) in pts with advanced GI tumors. Methods: Tivozanib was administered orally once daily in 4-week cycles (3 weeks on, 1 week off), with FOLFOX6 administered on days 1 and 15 of each cycle. Pts were allowed to continue tivozanib following discontinuation of FOLFOX6. Results: 22 pts (14 male/8 female; median age of 58 years [range, 40-75]) received 0.5 mg (n = 9), 1.0 mg (n = 3), or 1.5 mg (n = 10) tivozanib plus FOLFOX6. Pts received a median of 8.1 weeks (range, 0.1 - 43.1) of treatment. DLTs were observed in 2 pts receiving 0.5 mg tivozanib (reversible grade 3 diarrhea and grade 3 and 4 transaminase elevations, respectively) and in 2 pts receiving 1.5 mg tivozanib (reversible grade 3 seizures and grade 3 vertigo, respectively). Other grade 3/4 drug-related adverse events (AEs) included neutropenia, fatigue, and hypertension (n = 2 each); and pyrexia, pulmonary embolism, and thrombosis (n = 1 each). There was no indication that drug-related AEs in this study were more frequent or severe than those observed with tivozanib or FOLFOX6 alone. The MTD was 1.5 mg tivozanib with full dose FOLFOX6. The PK profiles of tivozanib, oxaliplatin, and 5-FU will be presented. Several durable partial responses were observed. Additional safety and efficacy data are being obtained in 8 pts currently being treated at the 1.5-mg dose level. Conclusions: The combination of tivozanib and FOLFOX6 is tolerable and safe, with tivozanib given at its recommended dose of 1.5 mg. Observed clinical activity merits further exploration in several GI tumors, and these studies are being planned. [Table: see text]

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