scholarly journals A multicenter phase 4 geriatric assessment directed trial to evaluate gemcitabine +/- nab-paclitaxel in elderly pancreatic cancer patients (GrantPax).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS10124-TPS10124
Author(s):  
Johannes Betge ◽  
Nicolai Haertel ◽  
Jing Chi-Kern ◽  
Sebastian Belle ◽  
Nadine Schulte ◽  
...  
Keyword(s):  
Functional Decline ◽  
Survival Rates ◽  
Best Supportive Care ◽  
Primary Objective ◽  
Ductal Adenocarcinoma ◽  
Duration Of Treatment ◽  
Open Label ◽  
Significance Level ◽  
Response To Chemotherapy ◽  
Open Label Phase

TPS10124 Background: Nab-paclitaxel/gemcitabine ( nab-P/gem) is an effective 1st line regimen for metastatic pancreatic ductal adenocarcinoma (mPDAC). Elderly mPDAC patients (pts) may as well benefit from nab-P/gem. Geriatric assessments to evaluate the functional reserve of these pts may allow individualization of treatment. Therefore, the aim of this study is to determine whether comprehensive geriatric assessments (CGAs) can predict the benefit from combined nab-P/gem therapy for elderly mPDAC pts in 1st line. A stratified treatment approach shall result in patient groups with a stable or improving CGA performance during the 1st cycle of treatment. Methods: GrantPax (NCT02812992) is a multicenter, open label phase 4 interventional trial with stratified parallel treatment groups (n = 45 per arm). The hypothesis is that individualized assessment directed treatment algorithms identify elderly pts (≥70 yrs), who benefit from combined nab-P/gem therapy. The study uses a CGA to stratify pts as GOGO, SLOWGO or FRAIL. Depending on test outcome, pts receive chemotherapy (GOGO: nab-P/gem; SLOWGO: gem mono) or best supportive care (FRAIL). After 1st cycle of chemotherapy (4 wks) a CGA and safety assessment will be performed to assign pts to their definite treatment arm. The primary objective is that CGA-stratified pts do not decline in their CGA performance in response to chemotherapy, measured as a loss of 5 points or less in Barthels activities of daily living (ADL1 vs. ADL2 during CGA core assessment). The expected proportion of pts with ADL decline in each treatment group is 6%. Under this assumption it shall be shown with 80% power at one-sided significance level alpha of 0.05 that the proportion of pts with functional decline is less than 20% (n = 43 per group; ADL decline: n = 2 per group). Secondary endpoints are CGA scores during the course of therapy (CGA1-4), response rates, safety, survival rates, duration of treatment, cumulative dose, quality of life and discrepancy between CGA strata estimation by the investigator and true CGA assessment. GrantPax is the first trial realizing a CGA-driven treatment to individualize cancer therapy for elderly pts. Clinical trial information: NCT02812992.

scholarly journals A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

2021 ◽  
Author(s):  
Noboru Yamamoto ◽  
Toshio Shimizu ◽  
Kan Yonemori ◽  
Shigehisa Kitano ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Liver Function ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Enzyme Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

Dasatinib 50 mg or 70 mg BID compared to 100 mg or 140 mg QD in patients with CML in chronic phase (CP) who are resistant or intolerant to imatinib: One-year results of CA180034

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7004-7004 ◽  
Author(s):  
N. P. Shah ◽  
D. W. Kim ◽  
H. M. Kantarjian ◽  
P. Rousselot ◽  
P. E. Dorlhiac-Llacer ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Response Rates ◽  
Primary Objective ◽  
Molecular Response ◽  
Duration Of Treatment ◽  
Open Label ◽  
Number Of Patients ◽  
One Year

7004 Background: Previous data with dasatinib (SPRYCEL®), a short-acting oral multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, have shown the safety and efficacy of the 70 mg BID dose in CP-CML patients. Surprisingly, phase-I data (NEJM 2006;354:2531) demonstrated complete hematologic (CHR) and major cytogenetic responses (MCyR) among CP-CML patients at total daily doses (TDD) of 100 mg and 140 mg in both the BID and QD schedule, despite the achievement of only transient inhibition of BCR-ABL by dasatinib when administered once daily. Methods: Patients with CP-CML resistant or intolerant to imatinib were randomized to one of 4 dasatinib arms: 1) 100 mg QD; 2) 50 mg BID; 3) 140 mg QD; 4) 70 mg BID. In this randomized, prospective, open-label trial, the primary objective compared the CyR rate among the BID and QD arms. Secondary objectives included comparison of the CyR rate between TTDs of 100 and 140 mg and the safety among the 4 arms. Results: 662 patients were randomized from July 2005 to March 2006 and received treatment. Response rates, with a median duration of treatment of 8 months, are shown below. Duration of CyR and progression-free survival were similar across all 4 arms. There was significantly less grade (Gr) 3–4 neutropenia (P=0.035), thrombocytopenia (P=0.001), anemia (P=0.032), and pleural effusions (P=0.028) in the 100-mg QD arm compared to the other 3 arms combined. No differences were seen across the 4 arms in the rates of other adverse events. There were fewer interruptions and reductions and the least number of patients discontinuing treatment for drug-related toxicity in the 100-mg QD arm. Conclusions: Dasatinib 100 mg QD offers the most favorable benefit-risk ratio in CP-CML. This trial provides the first evidence that intermittent kinase inhibition can achieve deep clinical remissions and is associated with an improved safety profile. One-year follow-up on all subjects, molecular response rates, and BCR-ABL mutation data will be presented. [Table: see text] [Table: see text]

A randomized, open-label, phase II study of lapatinib / capecitabine, lapatinib / vinorelbine, or lapatinib / gemcitabine in patients with ErbB2-amplified metastatic breast cancer progressing after taxane treatment: Results of an interim analysis (GLICO-0801 / EGF111792).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11087-e11087
Author(s):  
Henry Leonidas Gomez ◽  
Silvia P. Neciosup ◽  
Celia Tosello ◽  
Patricia Xavier ◽  
Yeni Neron do Nascimento ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Interim Analysis ◽  
Metastatic Breast ◽  
Primary Objective ◽  
Open Label ◽  
Open Label Phase ◽  
Hand Foot Syndrome ◽  
Number Of Cycles

e11087 Background: Lapatinib-capecitabine is approved for the treatment of ErbB2-amplified metastatic breast cancer (MBC) after failure to anthracyclines, taxanes and trastuzumab. GLICO-0801 evaluates different lapatinib-based chemotherapy combinations as 1st/2nd line treatment for ErbB2 amplified MBC progressing after taxane treatment. We present the results of a planned safety interim analysis. Methods: This is an open-label, randomized, international, phase II trial exploring lapatinib (L) 1250mg qd in combination with capecitabine 2000mg/m2 d 1-14 (Arm A) or vinorelbine 25mg/m2 d 1 and 8 (Arm B) or gemcitabine 1000mg/m2 d 1 and 8 (Arm C). Primary objective is to determine the clinical benefit rate (defined as CR+PR+SD for ≥24 weeks). This trial is registered at www.clinicaltrials.gov number: NCT01050322 Results: The first83 randomized patients (pts) (Arm A=29, B=28 and C=26) were included in this analysis. Of them, 65 (78%) have discontinued therapy with mean number of cycles of 4.7, 6.2 and 7.5 in arms A, B and C respectively. Eighteen (21%) pts are still on treatment. Median age was 52y (29-84); 80 pts (96%) had PS 0-1; 51 (61%) were postmenopausal. Fifty-six pts (67%) had visceral metastasis, 52 (63%) were treated as 2nd line therapy and 36 (43%) had received prior trastuzumab. Most reported adverse events (AE) (87%) were grade 1-2. The most common AE (any grade) in arm A: diarrhea 72%, hand-foot syndrome 45%, vomiting 39%, anemia 36%; in arm B: diarrhea 75%, neutropenia 68%, nausea 43%, vomiting 39%; in arm C: diarrhea 72%, neutropenia 60%, anemia 44%, increase in ALT 44%. The most frequent serious AE reported in arm A: diarrhea in 3 pts (10%) and thrombocytopenia in 2 pts (7%); in arm B: febrile neutropenia in 2 pts (7%) and in arm C: sepsis in 1 pt (4%). There was one toxic death related to chemotherapy in arm C. Conclusions: There were no unexpected toxicities so far in this trial with most AEs being mild to moderate and manageable. This interim analysis supports the continuation of the study.

Vinflunine maintenance therapy versus best supportive care (BSC) after platinum combination in advanced bladder cancer: A phase II, randomized, open-label study (MAJA study)—SOGUG 2011-02.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4674-TPS4674
Author(s):  
Sonia Maciá ◽  
Jesus Garcia-Donas ◽  
Albert Font Pous ◽  
Montserrat Domenech ◽  
Xavier Garcia del Muro ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Transitional Cell ◽  
Progression Free Survival ◽  
Best Supportive Care ◽  
Primary Objective ◽  
Open Label ◽  
Microtubule Inhibitor ◽  
Translational Study ◽  
First Line Therapy ◽  
Radiological Response

TPS4674 Background: Vinflunine is a novel microtubule inhibitor currently approved by EMA as treatment after platinum progression, in metastasic bladder cancer. It is distinguished from the other vinca-alkaloids because it binds relatively weakly to tubulin, suggesting an improved tolerance profile as a result of less neuropathy. Based on the fact that no cumulative toxicity is expected and the results reported in second-line, we aim to test the role of vinflunine in first line therapy, as maintenance treatment for patients who obtain clinical benefit after platinum. Methods: This is a multicenter, randomized, open label, proof-of-concept study that will be performed in 20 institutions members of the Spanish Oncology Genitourinary Group (SOGUG). Subjects will be randomized in a 1:1 ratio to receive vinflunine 320 mg/m2 every 21 days plus BSC vs BSC alone until disease progression. Vinflunine dose will be 280mg/m2 for patients with PS=1, age ≥ 75 years, prior pelvic radiotherapy or creatinine clearance Cr <60ml/min. Stratification factors are: 1) Scheduled dose at randomization (320 vs 280mg/m2) 2) Liver metastasis (Y/N). Main inclusion criteria are: Subjects ≥18 and< 80 years of age with histological diagnosis of transitional cell carcinoma of the urothelial tract and measurable disease with radiological response or stabilization after 6 cycles of a platinum containing doublet for metastasic/advanced disease. Primary objective will be progression free survival (PFS), considering as clinically relevant 6 months in experimental arm. To guarantee an overall type-1 α error (one side) no greater than 0.05 and a type II (β) error 0.1 for the primary endpoint of PFS, a sample size of 86 patients allocated in a 1:1 ratio is planned. Recruitment is scheduled to start by February 2012. A pharmacogenomic translational study will also be conducted.

A phase I/II study combining tosedostat with capecitabine in patients with metastatic pancreatic adenocarcinoma.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. TPS471-TPS471
Author(s):  
Andrea S. Teague ◽  
Manik A. Amin ◽  
Kian-Huat Lim ◽  
Albert C. Lockhart ◽  
Ashiq Masood ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Amino Acids ◽  
Phase I ◽  
Phase Ii ◽  
Primary Objective ◽  
Cellular Stress Response ◽  
Ductal Adenocarcinoma ◽  
Open Label ◽  
Pancreatic Cancer Cells ◽  
Dismal Prognosis

TPS471 Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Recent advances with fluorouracil in combination with oxaliplatin and irinotecan (FOLFIRINOX) and nab-paclitaxel combined with gemcitabine (AG) have improved survival in patients with PDAC. A fluorouracil-based regimen is recommended for patients who progress after a gemcitabine-based regimen. Tosedostat is an oral aminopeptidase inhibitor shown to have anti-proliferative effects in malignancies. Aminopeptidase inhibitors disrupt the cleavage of amino acids from peptides downstream of proteasomal degradation, preventing the recycling of amino acids needed for new protein synthesis. This leads to intracellular depletion of amino acids, resulting in a cellular stress response known as the amino acid deprivation response, which leads to apoptosis. Because pancreatic cancer cells frequently upregulate expression of these aminopeptidases, aminopeptidases inhibitors hold therapeutic promise. Methods: This is a single institution phase I/II open-label trial to evaluate the safety and tolerability of tosedostat plus capecitabine in patients with metastatic PDAC that have progressed after a gemcitabine-based regimen. The phase I part will be conducted in a dose de-escalation fashion, with two planned dose levels of tosedostat (120mg or 60mg) p.o. daily on days 1 to 21 with capecitabine 1000 mg/m2 p.o. BID on days 1 to 14 of a 21-day cycle. If more than one patient in the tosedostat (120 mg) cohort experiences a dose limiting toxicity (DLT), then 6 more patient will be enrolled to the tosedostat (60 mg) cohort. A total of 36 patients will be enrolled in the phase II portion. Primary objective of the phase I portion is to determine the maximum tolerated dose and DLTs of tosedostat and capecitabine combination therapy. Primary objective of the phase II portion is to determine the progression-free survival at 3 months. Secondary objectives are to determine the overall response rate, time-to-progression, overall survival and CA 19-9 response. Exploratory objectives are to explore the predictive molecular biomarkers for treatment response and to explore the prognostic biomarkers. Clinical trial: NCT02352831. Clinical trial information: NCT02352831.

Perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma: DANTE, a randomized, open-label phase II trial of the German Gastric Group of the AIO and the SAKK.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS4142-TPS4142
Author(s):  
Salah-Eddin Al-Batran ◽  
Claudia Pauligk ◽  
Ralf Hofheinz ◽  
Sylvie Lorenzen ◽  
Andreas Wicki ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Rank Test ◽  
R0 Resection ◽  
Open Label ◽  
Significance Level ◽  
Esophagogastric Cancer ◽  
Open Label Phase

TPS4142 Background: Perioperative FLOT chemotherapy has become a standard of care for locally advanced, resectable gastric cancer and adenocarcinoma of the GEJ. However, patient outcomes are still unsatisfactory and 5-year survival in T3-4 or nodal positive disease is still around 50%. Targeting the PD-1/PD-L1 pathway has proven active in different cancers, including esophagogastric cancer, and was associated with response rates in the 10-15% range in unselected, heavily pre-treated gastric cancer patients. Atezolizumab is a PD-L1 inhibitor with established efficacy and tolerability profiles. This study evaluates atezolizumab in the perioperative treatment of locally advanced, potentially resectable gastric or GEJ adenocarcinoma in combination with FLOT. Methods: This is a large, multinational, prospective, multicenter, randomized, investigator-initiated, open label phase II trial. Patients with locally advanced, potentially resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N-positive) without distant metastases are enrolled. Eligibility status is centrally evaluated. Patients are randomized 1:1 to 4 pre-operative 2-week cycles (8 weeks) of FLOT (Docetaxel 50 mg/m²; Oxaliplatin 85 mg/m²; Leucovorin 200 mg/m²; 5-FU 2600 mg/m²) followed by surgery and 4 additional cycles of FLOT plus atezolizumab at 840 mg every 2 weeks, followed by a total of 8 additional cycles of atezolizumab at 1200 mg every 3 weeks as monotherapy (arm A) or FLOT alone (arm B). Primary endpoint is time to disease progression or relapse after surgery (PFS/DFS) as assessed by the Kaplan-Meier-Method. The statistical design is based on a target HR of 0.68, a power of 0.8, and a significance level of p< 0.05 (1-sided log rank test). A total of 295 patients will be randomized. Main secondary endpoints are rates of centrally assessed pathological regression (rates of complete and nearly complete pathological regression), overall survival, R0 resection, and safety. Recruitment started in Sept 2018; by February 2019, a total of 27 patients have been randomized. Clinical trial information: NCT03421288.

Phase I study of NBTXR3 activated by radiotherapy in patients with advanced cancers treated with an anti-PD-1 therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3173-TPS3173 ◽  
Author(s):  
Colette Shen ◽  
Jessica Frakes ◽  
Jared Weiss ◽  
Jimmy J. Caudell ◽  
Trevor G Hackman ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Lung Metastases ◽  
Objective Response ◽  
Intratumoral Injection ◽  
Primary Objective ◽  
Open Label ◽  
Open Label Phase

TPS3173 Background: Despite the past decade of transformative advances in immuno-oncology, the response rate to checkpoint inhibitors (ICIs) remains low (~15%). There is significant interest in developing strategies to overcome resistance to these treatments, thus increasing response rate. Emerging evidence suggests that radiation therapy (RT) could potentially augment the antitumor response to ICIs through synergic effect. However, RT dose and ultimate efficacy are limited by toxicity related to exposure of healthy tissues. NBTXR3 is a first-in-class radioenhancer administered by direct intratumoral injection, designed at the nanoscale to increase RT dose deposition within tumor cells and RT-dependent tumor cell killing, without increasing surrounding normal tissue toxicity. Preclinical and early clinical data suggest NBTXR3 activated by RT can trigger an anti-tumor immune response, producing both local and systemic (abscopal) effects. We hypothesize that NBTXR3 activated by RT, in combination with anti-PD-1 therapy (R3/RT/PD-1), will act synergistically to maximize the local RT effect and produce a systemic response sufficient to increase the proportion of ICI responders or convert ICI non-responders to responders. Methods: This trial [NCT03589339] is a multicenter, open-label, phase I study to evaluate safety and tolerability of R3/RT/PD-1 in three cohorts: (1) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the HN field, (2) Lung metastases, or (3) Liver metastases, both from any primary cancer eligible for anti-PD-1 treatment. Approximately two-thirds of patients in each cohort will be anti-PD-1 non-responders. NBTXR3 injected volume is based on a percentage of gross tumor volume (GTV). The primary objective is to determine the R3/RT/PD-1 recommended phase 2 dose in each cohort. Secondary objectives are to evaluate anti-tumor response (objective response rate; ORR), safety and feasibility of NBTXR3 injection, and NBTXR3 body kinetic profile. Exploratory objectives will assess biomarkers of R3/RT/PD-1 response, including PD-L1 status by IHC, as well as mRNA and cytokine immune marker profiling. To date, three patients have been treated, one in cohort 1, two in cohort 2. Clinical trial information: NCT03589339 .

scholarly journals Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer

2016 ◽  
Vol 115 (7) ◽  
pp. 789-796 ◽  
Author(s):  
Angus G Dalgleish ◽  
Justin Stebbing ◽  
Douglas JA Adamson ◽  
Seema Safia Arif ◽  
Paolo Bidoli ◽  
...  
Keyword(s):  
Phase Ii ◽  
Immune Modulation ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Similar Rate ◽  
Adverse Event Reporting ◽  
Ductal Adenocarcinoma ◽  
Open Label ◽  
Open Label Phase ◽  
Intent To Treat

Abstract Background: Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma. Methods: Patients were randomised (2 : 1) to IMM-101 (10 mg ml−l intradermally)+GEM (1000 mg m−2 intravenously; n=75), or GEM alone (n=35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected. Results: IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44–1.04, P=0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33–0.87, P=0.01). Conclusions: IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study.

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