Phase I dose escalation study of immunoconjugate L-DOS47 in combination with pemetrexed/carboplatin in non-squamous non-small cell lung cancer (NSCLC) patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21680-e21680
Author(s):  
Afshin Dowlati ◽  
Chandra Prakash Belani ◽  
George R. Simon ◽  
Heman Chao ◽  
Sarina Anne Piha-Paul
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Objective Response ◽  
Safety Data ◽  
Maximum Tolerated Dose ◽  
Ammonia Toxicity ◽  
Current Phase ◽  
Urease Enzyme ◽  
Ph Increase ◽  
Nsclc Patients

e21680 Background: L-DOS47, a cancer therapeutic designed to exploit the acidic tumour extracellular environment, consists of urease conjugated to an anti-CEACAM6 camelid monoclonal antibody. The antibody serves as a targeting agent to deliver urease to tumor sites, while the urease enzyme converts urea, an abundant natural metabolite, into ammonia and generates a local pH increase. The combined effect of ammonia toxicity and pH increase is cytotoxic to cancer cells. An additive cytotoxic effect of L-DOS47 and pemetrexed/carboplatin has been observed against the A549 human lung adenocarcinoma cell line. L-DOS47 has been shown in a previous phase I clinical trial to be safe and well tolerated at doses up to 13.55 µg/kg. The current phase I study was designed to define the maximum tolerated dose of L-DOS47 in combination with pemetrexed/carboplatin. Methods: Stage IV (TNM M1a and M1b) histologically confirmed non-squamous NSCLC patients (aged ≥18 yrs, ECOG PS ≤1) received up to four cycles of L-DOS47 in combination with standard of care doses of pemetrexed/carboplatin. L-DOS47 was administered weekly over 21 days in each treatment cycle. Seven planned dosing cohorts (0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 μg/kg) employed a standard 3+3 design for the first two and the last two cohorts, and an accelerated 1 + 2 design for the middle three cohorts. Dose levels of L-DOS47 were escalated following a review of safety data by the Trial Steering Committee. Results: Fourteen (14) patients were enrolled across 6 dosing cohorts before recruitment was halted. Median age was 65.1 years, with 50.0% male and 78.6% Caucasian. 57.1% of patients had an ECOG score of 0, and 42.9% had an ECOG score of 1. The maximum tolerated dose (MTD) could not be determined as none of the patients experienced a dose limiting toxicity (DLT). 50.0% of patients experienced at least one treatment emergent adverse event (TEAE) assessed as study drug-related, with 14.3% of patients experiencing at least one grade 3/4 drug-related toxicity. Of 12 patients evaluable for efficacy, 5 patients (41.7%) had a partial response (PR), 4 patients (33.3%) experienced stable disease (SD) and 3 patients (25.0%) had progressive disease (PD). The objective response rate is 41.7%. The clinical benefit rate is 75.0%. Conclusions: L-DOS47, in combination with pemetrexed/carboplatin, appears to be well tolerated with promising anti-tumor activity against non-squamous NSCLC. Clinical trial information: NCT02309892.

Taletrectinib (AB-106; DS-6051b) in metastatic non-small cell lung cancer (NSCLC) patients with ROS1 fusion: Preliminary results of TRUST.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9066-9066
Author(s):  
Caicun Zhou ◽  
Huijie Fan ◽  
Yongsheng Wang ◽  
Huijuan Wu ◽  
Nong Yang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Blood Cell ◽  
Phase I ◽  
White Blood Cell ◽  
Objective Response ◽  
Clinical Activity ◽  
Phase I Trials ◽  
Transaminase Elevation ◽  
Nsclc Patients ◽  
Clinical Trial Information

9066 Background: Taletrectinib (AB-106; DS-6051b) is a potent, selective ROS1/NTRK inhibitor. In two phase I trials, NSCLC patients (pts) with ROS1 fusion who received taletrectinib as first line ROS1 TKI had an objective response rate (ORR) of 66.7% (6/9) and median progression-free survival (PFS) of 29.1 mo (Sai-Hong Ignatius Ou et al., JTO Clinical and Research Reports, 2020). TRUST (NCT04395677) is an ongoing, multicenter, phase II study of taletrectinib in Chinese NSCLC pts with ROS1 fusion. Methods: The ROS1 TKI naïve or crizotinib pre-treated NSCLC patients with ROS1 fusion were treated with taletrectinib 400 or 600 mg QD. ROS1 testing was performed in each center and confirmed by central lab using RT-PCR. The primary endpoint was ORR (complete response [CR] + partial response [PR]) by IRC assessment. Secondary endpoints were disease control rate (DCR; CR + PR + stable disease), PFS and safety, etc. The pharmacokinetics (PK) of taletrectinib following 400 or 600 mg QD regimen was also evaluated. Results: As of the data cutoff (15 Jan 2021), 22 pts had received taletrectinib treatment. Median age was 54.5 years (range, 32-77 years;); 18.2% (4/22) had central nervous system metastases; ECOG performance status was 0 in 13.6% (3/22) of pts and 1 in 86.4% (19/22) of pts. Most pts (54.5%, 12/22) had prior systematic chemotherapy; 31.8% (7/22) of pts had prior crizotinib treatment. ORR by investigator among the crizotinib naïve pts with tumor assessment (N = 11) was 100% (95% CI, 72%-100%); 81.8% (18/22) of pts had treatment-emergent adverse events (TEAEs), including nausea, vomiting, diarrhea, transaminase elevation, white blood cell count decrease/neutrophil count decrease, etc. 13.6% (3/22) were grade ≥ 3, including fatigue (4.5%, 1/22), white blood cell decrease (4.5%, 1/22) and transaminase elevation (4.5%, 1/22).TEAEs led to dose interruption in 3 pts (13.6%), including dose reduction in 2 pts (9.1%). Taletrectinib in plasma approximately reached steady state on Cycle 1 Day 8 with 2- to 3- fold accumulations of exposure, which was consistent with results observed in the phase I trials. Conclusions: Taletrectinib demonstrated promising clinical activity with high ORR and good tolerability in ROS1 fusion positive NSCLC patients. The safety and PK profiles following taletrectinib treatment was generally consistent with the phase I trials. Clinical trial information: NCT04395677. Clinical trial information: NCT04395677.

Anlotinib combined with pemetrexed and carboplatin as first-line treatment in advanced nonsquamous non-small cell lung cancer (NSCLC): ALTER L012.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21040-e21040
Author(s):  
Qiming Wang ◽  
Xiuli Yang ◽  
Tianjiang Ma ◽  
Qiumin Yang ◽  
Chenghui Zhang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Treatment Naïve ◽  
Nsclc Patients ◽  
First Line Treatment

e21040 Background: The anti-angiogenic drug bevacizumab combined with chemotherapy has achieved positive results in previous studies. In particular, the median progression-free survival (PFS) for EGFR-negative patients was increased to 8.3 months in the BEYOND study. Unlike bevacizumab, anlotinib is a novel multitarget tyrosine kinase inhibitor and can be conveniently orally administered. In the phase III trial ALTER 0303, anlotinib significantly improved overall survival (OS) and PFS in advanced NSCLC patients. This exploratory study aims to establish the efficacy and safety of anlotinib in combination with pemetrexed and carboplatin as first-line treatment in advanced non-squamous NSCLC. Methods: This is a multi-center, single-arm clinical trial. Adults with treatment-naive, histologically confirmed stage IIIB-IV non-squamous NSCLC, ECOG 0-1, and without known sensitizing EGFR/ALK alterations are included. Patients received anlotinib (12 mg p.o., QD, d1 to 14, 21 days per cycle) combined with pemetrexed (500 mg/m2, iv, d15-21, Q3W) + carboplatin (AUC = 5, iv, d15-21, Q3W) for 4 cycles followed by anlotinib and pemetrexed maintenance until disease progression (PD). The primary endpoint was PFS. Secondary endpoints were OS, objective response rate (ORR), disease control rate (DCR) and safety. Results: Between Mar 2019 and Dec 2020, 40 patients were enrolled in six centers and 31 of them have received at least one tumor assessment. Median age was 62 (33, 75); 66.7% male, 11.1% brain metastasis. At data cutoff (Dec 31, 2020), patients were followed up for a median of 8.26 months. Median PFS was 10.5 months (95% CI: NE, NE); ORR was 67.7% (0 CR, 21 PR), DCR was 96.8% (0 CR, 21 PR, 9 SD) and median OS was NE. The most common Grade ≥ 3 AEs were hypertension 22.2%, neutropenia 19.44%, myelosuppression 11.1%, thrombocytopenia 8.33%, leukopenia 5.56%, hand-foot syndrome 5.56% and there were no Grade 5 toxicities. Conclusions: This study finds that anlotinib plus pemetrexed and carboplatin can significantly improve PFS and ORR compared to standard chemotherapy for treatment-naive non-squamous NSCLC patients. The combination was well tolerated, and the AEs were manageable. The follow-up time is not sufficient, and the OS outcomes need further evaluation. Clinical trial information: NCT03790228.

CTNI-47. INTERIM RESULTS OF NCT03011671: A MULTI-INSTITUTIONAL PHASE I STUDY OF ACETAZOLAMIDE WITH TEMOZOLOMIDE IN ADULTS WITH NEWLY DIAGNOSED MGMT-METHYLATED MALIGNANT GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi70-vi70
Author(s):  
Bakhtiar Yamini ◽  
Seán Lyne ◽  
Riley Driscoll ◽  
Giovanna Bernal ◽  
Longtao Wu ◽  
...  
Keyword(s):  
Phase I ◽  
Malignant Glioma ◽  
Phase I Study ◽  
Objective Response ◽  
Controlled Study ◽  
Current Phase ◽  
Newly Diagnosed ◽  
Biomarker Analysis ◽  
Secondary Endpoints ◽  
Grade Iii

Abstract Preclinical studies indicate that up-regulation of carbonic anhydrase (CA) by temozolomide (TMZ), via a mechanism requiring the proto-oncogene BCL-3, promotes resistance to therapy in glioblastoma (GBM) cells. Moreover, the CA inhibitor, acetazolamide (ACZ), sensitizes patient-derived GBM cells and xenografts to TMZ. These findings led to the current Phase I study investigating the safety and efficacy of adding ACZ to adjuvant TMZ in patients with newly diagnosed, MGMT-methylated malignant glioma. 24 patients were enrolled (23 GBM and one Grade III IDH-mutant astrocytoma), median age was 53.5 and mean KPS 91. ACZ was given on days 1-21 of each adjuvant TMZ cycle (250 mg BID days 1-7, increased to 500 mg BID days 8-21). No patient experienced the primary outcome of regimen limiting toxicity (RLT) and there were only three grade III adverse events deemed likely unrelated to ACZ. For the secondary endpoints of overall and progression free survival (OS and PFS, respectively), only the 23 GBM patients were included (22 IDH-wildtype and 1 IDH-mutant). From diagnosis, median PFS was 18.8 months (95% CI: 10.4-23.0) and median OS was 25.0 months (95% CI: 19.9-28.4). Median time from diagnosis to consent was 2.9 months. As of April 2021, only 7 of 23 deaths had occurred. 2-year OS% was 68.2%. Further analysis of secondary endpoints including 6-month objective response rate (ORR) and biomarker analysis of BCL-3 by IHC will be available in the coming months. In sum, the data indicate that addition of ACZ to TMZ is safe and does not lead to reduced TMZ dosing. Also, compared to historical data, interim outcomes suggest that addition of ACZ may substantially improve PFS and 2-year overall survival. These findings support the hypothesis that ACZ acts as a chemosensitizer of alkylating chemotherapy in GBM and support examination of this regimen in a randomized, placebo-controlled study.

Final results from a phase I trial of ixabepilone in patients with advanced malignancies and lymphoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2039-2039
Author(s):  
C. Aghajanian ◽  
O. O’Connor ◽  
M. Cohen ◽  
R. Peck ◽  
H. Burris
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Phase Ii Studies ◽  
Grade 3

2039 Background: Ixabepilone is the first analog in a new class of antineoplastic agents, the epothilones, which stabilizes microtubules and induces apoptosis. Ixabepilone has shown clinical activity in a broad range of tumors. Methods: This Phase I trial was designed to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), efficacy, safety, pharmacokinetics and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or lymphoma. Eligible patients were aged ≥18 years with histologically/cytologically confirmed non-hematologic cancer, or a pathologic diagnosis of relapsed/primary refractory non-Hodgkin’s lymphoma (NHL) or relapsed/primary refractory mantle cell lymphoma, with ≤CTC Grade 1 neuropathy. Ixabepilone doses ranged from 7.5–65 mg/m2. Response was assessed every 6 weeks using RECIST. DLT was defined as Grade 4 neutropenia and/or febrile neutropenia, thrombocytopenia, ≥Grade 3 nausea/vomiting and non-hematologic toxicity, or treatment delay of >2 weeks due to delayed recovery. Results: Of 61 patients (median age 58, range 18–81), 75% had solid tumors; 25% had lymphoma. 98% and 67% of patients had received one or ≥ two prior chemotherapy regimens, respectively. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m2. The most common DLTs were neutropenia, myalgia, arthralgia and stomatitis/pharyngitis. A total of eight patients (13%) achieved a durable objective response. Complete responses were achieved in two patients with primary peritoneal cancer and NHL. A partial response was seen in six patients. The most common Grade 3/4 treatment-related adverse events (only observed at doses ≥40 mg/m2) were sensory neuropathy (13%), fatigue (13%), myalgia (10%), arthralgia (7%), nausea (5%), febrile neutropenia (5%) and neutropenia (5%). Recovery to baseline or ≤Grade 1 neuropathy occurred in some patients. Conclusions: The recommended dose of ixabepilone for the initiation of Phase II studies based on this study is 50 mg/m2 over 1 hour every 3 weeks. Ixabepilone demonstrates promising safety in patients with solid tumors or lymphoma who have failed standard therapy. Encouraging activity was reported in several tumor types. [Table: see text]

TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies: A phase I/II dose finding and biomarker study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3563-3563 ◽  
Author(s):  
E. Angevin ◽  
J. A. Lopez ◽  
A. Pande ◽  
C. Moldovan ◽  
M. Shi ◽  
...  
Keyword(s):  
Phase I ◽  
Kinase Inhibitor ◽  
Sinus Bradycardia ◽  
Safety Data ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Primary Objective ◽  
Dose Finding ◽  
Minor Response ◽  
Suprarenal Mass

3563 Background: TKI258 is a potent receptor tyrosine kinase inhibitor (TKI) that selectively targets VEGFR, PDGFR, FGFR, CSF1R, c-KIT, RET, TrKA, and FLT3. Compared to other TKI agents, TKI258 additionally targets FGFR. FGF has been reported as an important escape mechanism of anti-VEGFR therapies. Methods: The primary objective of this phase I was to determine the maximum tolerated dose (MTD) of TKI258, administered orally on a 5 days on / 2 days off schedule in repeated 28 day cycles, in mRCC pts refractory to standard therapies. A two-parameter Bayesian logistic regression model and safety data for at least 21 pts will be used to determine MTD. Results: A phase I study is ongoing. As of December 2008, 11 pts (9 m, 2 f), median age: 55 (29–66 yrs) have been enrolled. Four pts have been treated at 500 mg/day (start dose): 2 are ongoing at cycle (C) 7; 1 pt discontinued due to PD and 1 due to sinus bradycardia. Five pts received 600 mg/day: 2 DLTs (G4 hypertension and G3 fatigue - pts discontinued) leading to dose reduction of all patients to 500mg/day; 2 pts in C5 and C4, 1 pt discontinued for PD. Two pts just entered the extension cohort at 500 mg. Other toxicities ≥G2 included fatigue, nausea, vomiting, diarrhea, neutropenia, folliculitis and dizziness. PK data showed CMax range (180–487 ng/mL, n = 8), and AUC range (2200–8251 ng/mL*h). Preliminary biomarker data indicated pts had high baseline VEGF (506 ± 203 pg/ml, n=6) and bFGF (220 ± 185 pg/ml, n = 6) levels, which may reflect failure of previous anti-VEGF agents. Induction of plasma FGF23 levels, a pharmacodynamic biomarker of FGFR1 inhibition, was observed in pts from the first 500 mg/day dosing cohort. Preliminary evidence of efficacy is observed with one minor response (-17% at C4), 4 stable disease and 1 dramatic shrinkage/necrosis of some target lesions (lymph node & suprarenal mass). Conclusions: TKI258 500mg/day seems a feasible schedule in heavily pre-treated mRCC patients with some indications of clinical benefit. These preliminary findings will be confirmed in the extension cohort. [Table: see text]

A phase I/II study to evaluate the ability of decitabine and panobinostat to improve temozolomide chemosensitivity in metastatic melanoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3056-3056
Author(s):  
Chang Xia ◽  
Douglas Earl Laux ◽  
Jeremy Michael Deutsch ◽  
Melanie Frees ◽  
Brian Smith ◽  
...  
Keyword(s):  
Phase I ◽  
Metastatic Melanoma ◽  
Performance Status ◽  
Safety Data ◽  
Stage Iv ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Primary Endpoints ◽  
Number Of Cycles ◽  
Ecog Ps

3056 Background: Epigenetic gene regulation is likely a contributing mechanism of cancer initiation and progression. Emerging evidence indicates that epigenetics may also play a key role in the development of chemoresistance in melanoma. We proposed combining the histone deacetylase inhibitor panobinostat (PT) and the demethylator decitabine (D) to overcome the development of epigenetic mediated temozolomide (TMZ) resistance in metastatic melanoma. Methods: Eligible patients must be ≥18, stage IV melanoma, and naïve or previously treated, with good performance status (ECOG ≤ 2) and normal organ functions. Patients with previous exposure to TMZ were allowed on study. The study includes the dose escalation of D and PT followed by expansion cohorts. D (0.1mg/kg SQ, 0.2mg/kg SQ) on days 1, 3, 5, 8, 10,12, PT (10mg PO, 20mg PO, 30mg PO) Q96h starting day 8, and TMZ 150mg/m2 PO daily on days 9-13 of each 42 day cycle. TMZ was increased to 200mg/m2 in the absence of grade 2 thrombocytopenia. Primary endpoints of phase I study are to determine the toxicity, safety and maximum tolerated dose (MTD) of the D, PT and TMZ combination. Results: To date, the phase I portion of this trial is completed. We report on the safety data for this combination. 17 patients received treatment (1st cohort: 5; 2nd cohort: 4; 3rd cohort: 4; 4th cohort: 4 ). M:F 11:6. Median age: 56 (32-77); Median ECOG PS: 1; 82% of the patients received at least one cycle (n=14). Median number of cycles given: 2 (0-6). To date, no DLTs have occurred. The MTD was not reached. The only grade (G) 4 adverse event (AE) is neutropenia on a patient in cohort 3 and it resolved within 3 days. G3 AEs included lymphopenia (n=4, 23%), anemia (n=2, 12%), leukopenia (n=2, 12%) and fatigue (n=2, 12%). Common G2 toxicities were leukopenia (n=5, 30%), neutropenia (n=4, 23%), nausea (n=4, 23%) and lymphopenia (n=3, 18%). Conclusions: The combination of D, PT, and TMZ appears to be safe and well-tolerated. The recommended dose for the phase II study remains to be determined.

A first-in-human, phase I safety and pharmacokinetic study of genz-644282, a non-camptothecin topoisomerase I inhibitor, in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2534-2534
Author(s):  
Hyo S. Han ◽  
Antoinette R. Tan ◽  
Glen J. Weiss ◽  
Daniel Sullivan ◽  
Jonathan R. Strosberg ◽  
...  
Keyword(s):  
Phase I ◽  
Dna Cleavage ◽  
Topoisomerase I ◽  
Safety Data ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Ring Structure ◽  
Small Cell ◽  
Small Cell Lung ◽  
Minor Response

2534 Background: The approved topoisomerase I (TopI) inhibitors (irinotecan and topotecan) are camptothecin derivatives. The lactone ring structure of camptothecins negatively impacts their clinical potential.Genz-644282 is a novel non-camptothecin that induces TopI-DNA cleavage complexes at similar as well as unique genomic positions; that are more persistent. This study was designed using a pharmacokinetic-pharmacodynamic (PK-PD) model to predict the maximum tolerated dose (MTD). Methods: A PK-PD relationship of Genz-644282 to inhibit tumor growth was derived (Simeoni, Can Res 2004). Using an accelerated titration design, cohorts of 1, 3 or 6 patients received 3 weekly doses of Genz-644282 on a 28 day schedule starting with 0.5 mg/m2. After MTD on the 28 day schedule was exceeded, 21 day schedule was initiated. Results: 49 patients (N=44 data available: 26M :18F) were dosed. Tumor types were colorectal (15), breast (5), small cell lung (SCLC 3), non-small cell lung (4), others (17). As predicted from the PK-PD model 8 cohorts were evaluated on the 28 day schedule before defining the MTD. The MTD was 8 mg/m2 and 9 mg/m2 for the 28 day and 21 day schedules, respectively. Dose limiting toxicities that determined the MTD were: gr 4 thrombocytopenia (n=2); gr 2 thrombocytopenia (n=1) and gr 4 neutropenia (n=1) both of which resulted in ≥72h delays in initiating cycle 2. Treatment emergent adverse events (>10%) were nausea (45%), fatigue (39%), anorexia (32%), anemia (27%), vomiting (23%), thrombocytopenia (18%), diarrhea (16%), dehydration (16%), hyperglycemia (16%), cough (16%), dyspnea (14%), depression (11%) and hyponatremia (11%). Efficacy data suggest 2 responders with SCLC (1 minor response;1 complete response), and 2 patients (breast, gastric) with stable disease (≥ 6 months). PK data show a Genz-644282 half-life of approximately 50 h, a linear dose-exposure relationship, and no accumulation in between doses. Conclusions: Genz-644282 is a non-camptothecin TopI inhibitor in phase I development with ongoing expansion phase. The emerging pk, efficacy and safety data are suggestive of a distinct clinical profile of Genz-644282 from the camptothecins.

A phase I study of sorafenib with FOLFIRI as first-line therapy for metastatic colorectal cancer (mCRC): Safety and efficacy results.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3633-3633
Author(s):  
Jean Alfred Maroun ◽  
Derek J. Jonker ◽  
M. Christine Cripps ◽  
Timothy R. Asmis ◽  
Rakesh Goel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Objective Response ◽  
Progression Free Survival ◽  
Response Duration ◽  
Maximum Tolerated Dose ◽  
Future Research ◽  
Curative Surgery ◽  
First Line Therapy

3633 Background: Phase I dose escalation to a maximum planned dose (MPD) o determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended-phase-II-dose (RP2D) and preliminary efficacy of sorafenib and FOLFIRI (irinotecan reduced-dose) in metastatic colorectal cancer (mCRC) patients. Methods: Starting doses: irinotecan 80 mg/m2 iv d1, sorafenib 400 mg po twice daily (bid, continuous), starting day 2. Escalations based on toxicity observed at the previous dose level (DL) up to: irinotecan 100 mg/m2 and sorafenib 800 mg bid. DLT was evaluated within the 1st study cycle (1 cycle = 2 FOLFIRI treatments). Results: 5 cohorts were concluded. All 16 ECOG PS 0-1 patients (9/7 men/women; 2/14 rectal/colon) with median age of 64, discontinued study: 10 (62%) disease progression, 4 (25%) toxicity, 1 curative surgery, 1 comorbidities. The dose levels of irinotecan (mg/m2, day1) and sorafenib (mg/day, bid, day 2-28) studied were DL1-80/400, DL2-80/600, DL3-90/600, DL4-100/600 and DL5-100/800, repeated every 4 weeks, 3 patients/DL. No DLT was observed. The MTD was not reached at the MPD (DL5). The most common ≥Gr2 treatment related adverse events (AEs) were: neutropenia 81%, HFS 69%, leucopenia 50%, fatigue 38%, anemia 31%, constipation 31%, nausea/vomiting 31%, mucositis 31%, diarrhea 25%, hypophosphatemia 25%. The most severe treatment related AEs were: Gr4: neutropenia 2 (12.5%); pulmonary embolism 1 (6%); Gr3: HFS 9 (56%), neutropenia 3 (19%), leucopenia 3 (19%), hypophosphatemia 3 (19%). Objective response rate was 56% (9 of 16 patients, 95%CI; 33-77%). Response duration was 13 months (95%CI; 5-17). Median progression-free survival and overall survival were 11 months (95%CI; 6-17) and 25 months (95%CI; 15-34), respectively. Conclusions: Combination therapy with S and modified FOLFIRI in these patients is well tolerated and demonstrates clinical efficacy at the MPD. The MTD was not reached at the MPD. Future research of this combination is warranted. Supported by Bayer Healthcare Pharmaceuticals. Clinical trial information: NCT00780169.

The mitochondrial metabolism inhibitor CPI-613 in combination with mFOLFIRINOX for pancreatic adenocarcinoma.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 264-264
Author(s):  
Angela Tatiana Alistar ◽  
Rodwige Desnoyer ◽  
Ralph D'Agostino
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Trial ◽  
Phase I ◽  
Response Rate ◽  
Treatment Options ◽  
Objective Response ◽  
Stage Iv ◽  
Phase I Clinical Trial ◽  
Glutamine Metabolism ◽  
Metastatic Pancreatic Cancer

264 Background: Stage IV pancreatic cancer is a lethal disease with limited treatment options. Current standard practice is combination chemotherapy with FOLFIRINOX or Gemcitabine + Abraxane. Despite these two new treatment options, the response rate and survival are limited in stage IV pancreatic cancer. The glycolic and mitochondrial metabolisms are aberrant in pancreatic cancer and translate into chemo-resistance. Inhibition of glutamine metabolism can potentially synergize with therapies that increase intracellular reactive oxygen species such as chemotherapy. CPI -613 is a novel anti-mitochondrial developed by Cornerstone Pharmaceuticals. Methods: A phase I clinical trial with mFOLFIRINOX+ CPI-613 in never treated for stage IV pancreatic cancer patients was initiated. The goals of this phase 1trial are: (1) To determine the Maximum Tolerated Dose (MTD) of CPI-613, when used in combination with mFOLFIRINOX, in patients with metastatic pancreatic cancer, (2) To assess the safety of CPI-613/ mFOLFIRINOX combination in patients with metastatic pancreatic cancer, and (3) To obtain preliminary data on efficacy of treatment with CPI-613/ mFOLFIRINOX Results: The MTD for CPI 613 was identified at 500mg/m2. The treatment combination is feasible and well-tolerated. The combination treatment was not found to have higher toxicity than FOLFIRINOX alone. The objective response rate was 53.9 % which is higher than FOLFIRINOX alone (reported as 31.6%). One patient has a complete radiologic and clinical response and two other patients have near complete responses. Conclusions: The preliminary efficacy data of this phase I clinical trial will inform a multi-institutional randomized phase II study of FOLFIRINOX vs. m FOLFIRINOX+ CPI613 in the near future. Clinical trial information: NCT01835041.

A phase I/II study to assess the safety and efficacy of pazopanib (PAZ) and pembrolizumab (PEM) in patients (pts) with advanced renal cell carcinoma (aRCC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4506-4506 ◽  
Author(s):  
Simon Chowdhury ◽  
David F. McDermott ◽  
Martin Henner Voss ◽  
Robert E. Hawkins ◽  
Paola Aimone ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Renal Cell Carcinoma ◽  
Phase I ◽  
Liver Toxicity ◽  
Maximum Tolerated Dose ◽  
Limited Information ◽  
Safety And Efficacy ◽  
Sequential Schedule ◽  
Anti Tumor Activity ◽  
Clinical Trial Information

4506 Background: PAZ is indicated for the treatment of aRCC. The combination of an anti-angiogenic agent and immunotherapy may improve anti-tumor activity. We report preliminary safety and efficacy results of the phase I part of the study. Methods: Twenty pts were originally enrolled in cohorts A and B assessing PAZ 800 mg and 600 mg, respectively, both with 2mg/kg (Q2W and then Q3W) PEM to determine the maximum tolerated dose. Due to dose limiting liver toxicity, cohort C was opened to assess if the sequential schedule of 9 weeks PAZ run-in followed by PAZ+PEM would improve safety. Strict safety criteria for initiating PAZ+PEM were set. The data from this ongoing study are presented given the limited information available on the combination of TKI + PD-1 inhibitors in RCC. Results: Overall, 35 pts were treated; 5 out of 15 pts in cohort C received PAZ+PEM at the data cut-off. Three dose-limiting toxicities (DLT) occurred in cohort C in pts receiving PAZ+PEM; updated DLTs in all cohorts are reported in Table. G3/4 AEs were observed in 90% of pts in cohorts A and B and in 80% of pts in cohort C receiving PAZ+PEM. No G3/4 ALT/AST elevation was reported in cohort C PAZ+PEM while they were observed in 70% and 60% in cohorts A and B, respectively. Best overall response (CR+PR) was reported in 6, 2 and 1 pts receiving PAZ+PEM in cohorts A, B and C, respectively. Conclusions: Results from cohorts A and B showed significant hepatotoxicity. The sequential schedule PAZ → PAZ+PEM has shown reduced hepatotoxicity and preliminary signs of efficacy but overall limited tolerability. PAZ+PEM is not suitable to test in a larger cohort. Clinical trial information: 2013-003785-14. [Table: see text]

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