A multisite clinical trial of spectroscopic MRI-guided radiation dose escalation for newly-diagnosed glioblastomas.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2018-2018
Author(s):  
Hui-Kuo George Shu ◽  
Eric Albert Mellon ◽  
Lawrence Kleinberg ◽  
Saumya S Gurbani ◽  
Karthik K Ramesh ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Escalation ◽  
Idh1 Mutation ◽  
Resonance Spectroscopy ◽  
Newly Diagnosed ◽  
Eligibility Criteria ◽  
Normal Appearing White Matter ◽  
Increased Risk ◽  
Grade 3 ◽  
Poor Outcomes

2018 Background: Glioblastoma (GBM) is the most common adult primary malignant brain tumor. These pts have poor outcomes [median overall survival (OS) ̃ 16 months] despite radiation therapy (RT) to 60 Gy and temozolomide (TMZ). Magnetic resonance spectroscopy (MRS) measures levels of specific metabolites in the brain including choline (Cho) and N-acetyl aspartate (NAA). Previously, we found that high Cho/NAA ratios can aid in localizing regions of brain at high risk for GBM recurrence that may not be appreciated on standard contrast-enhanced (CE) MRI. Based on this finding, we conducted a clinical trial to assess the feasibility and safety of using an advanced volumetric MRS technique termed spectroscopic MRI (sMRI) to guide RT dose escalation for newly-diagnosed GBMs. Methods: Our clinical trial (NCT03137888) funded by the NCI (RO1CA214557) enrolled pts at 3 institutions (Emory U, U Miami, Johns Hopkins U) from 5/2017 to 4/2019. This study was approved by the IRB at each respective institution. Eligibility criteria included newly-diagnosed GBM pts ≥ 18 years of age with a tumor site that could be adequately imaged by sMRI. Cho/NAA ratio was normalized to the contralateral normal appearing white matter (NAWM). For RT planning, standard gross tumor volumes (GTV1 & 2) were defined based on T2-FLAIR and T1 CE MRIs and 5 mm margins were added to generate clinical tumor volumes (CTV1 & 2). GTV3 ( = CTV3, sMRI-defined) was generated by the union of residual CE tumor and Cho/NAA ≥ 2x NAWM. To remain eligible, CTV3 was required to be ≤ 65 cc. Planning target volumes (PTVs) were generated by applying a 3 mm margin around CTVs. 50.1, 60 and 75 Gy in 30 fractions were prescribed to PTV1, PTV2 and PTV3, respectively. All pts received standard concurrent/adjuvant TMZ. Survival curves were generated by the Kaplan-Meier method. Toxicities were assessed according to CTCAE v4.0. Results: 30 pts met eligibility and were treated on study. Mean/median ages were 56.4/58.9 years. 9 pts (30%) were MGMT methylated; 2 pts (6.7%) harbored an IDH1 mutation. With median followup of 21.4 months in censored pts, median OS was 23.0 months. 11 of 30 pts were documented to have experienced grade 3 or greater toxicities that were at least possibly due to their treatment. Of the 7 pts who experienced these by 9 months post-RT, most were attributable to TMZ (thrombocytopenia x 4, thrombocytopenia/neutropenia x 1, transaminitis x 1) and only one case (headaches/fatigue x 1) could potentially be ascribed to RT. Increased risk of pseudoprogression or radiation necrosis, especially beyond 3 months post-RT, was noted but these were clinically manageable and did not result in toxicity ≥ grade 3. Conclusions: Dose-escalated RT to 75 Gy guided by sMRI appears feasible and safe for pts with newly-diagnosed GBMs. OS outcome is also quite promising and warrants additional testing. Based on these results, a phase II randomized trial is planned at ECOG-ACRIN (EAF211). Clinical trial information: NCT03137888.

scholarly journals Predicting Induction Toxicity with 7+3: Analysis of SWOG Trial S1203

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1403-1403 ◽  
Author(s):  
Megan Othus ◽  
Guillermo Garcia-Manero ◽  
Frederick R. Appelbaum ◽  
Harry P. Erba ◽  
Roland B. Walter
Keyword(s):  
Clinical Trial ◽  
Research Funding ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Cell Counts ◽  
Increased Risk ◽  
Multivariable Models ◽  
Grade 3 ◽  
Baseline Covariates ◽  
Support Research

Abstract Background: Prior work has shown that multivariable models can have reasonably high accuracy in predicting early deaths (deaths within 28 days of starting induction, defined as treatment-related mortality [TRM]) following intensive AML chemotherapy. These models can be used to derive a TRM score reflective of the probability of TRM with intensive AML therapy, and such scores can be used to make informed treatment decisions and as explicit eligibility criteria in AML protocols. The degree to which non-fatal toxicities can be predicted is unknown. It is also not known which patient characteristics are most strongly associated with occurrence of non-fatal toxicities following induction chemotherapy. Here, we examined these questions using data from the most recent SWOG Phase III with a 7+3 arm. Patients and Methods: We analyzed 260 eligible patients randomized to the 7+3 arm SWOG trial S1203 who received the first cycle of protocol therapy. 7+3 was per contemporary standard when the trial was opened in 2012: 100mg/m2 cytarabine on days 1-7 and 90mg/m2daunorubicin on days 1-3. Toxicities were reported using CTCAE version 4.0. We used logistic regression models to model toxicity incidence and evaluated the predictive accuracy of the models with the area under the receiver operating characteristic curve (AUC). We note that AUC of 0.5 is what would be expected with random chance or using a coin flip to make a decision, while an AUC of 1 denoted perfect prediction. We evaluated the following baseline covariates (modeled quantitatively unless otherwise specified): age at study registration, gender, Zubrod performance status (0-1 versus 2-3), pre-study white blood cell counts (WBC), pre-study platelets, pre-study marrow blasts, secondary vs. de novo AML, cytogenetic risk, and NPM1+ and FLT3-ITD- versus other NPM1/FLT3-ITD status. For toxicities with lower incidence, the number of covariates included in multivariable models was proportionate to one covariate per 10-15 patients with a toxicity. Toxicities were reported using the contemporary CTCAE version 4.0. Only toxicities observed during the first cycle of induction are analyzed below. Results: We evaluated the incidence grade 3 or higher thrombocytopenia (n=180, 70%), infection (n=166, 64%), anemia (n=159, 61%), neutropenia (n=145, 56%), lymphopenia (n=92, 35%), electrolyte abnormalities (n=66, 25%), liver abnormalities (n=37, 14%), cardiovascular abnormalities (n=20, 8%), constitutional symptoms (n=19, 7%), skin abnormalities (n=18, 7%), mucositis (n=17, 7%), GI tract abnormalities (n=16, 6%), pulmonary abnormalities (n=14, 5%), pain (n=13, 5%), endocrine abnormalities (n=12, 5%), bleeding (n=12, 5%), neurologic abnormalities (n=10, 4%), nausea/vomiting (n=7, 3%), kidney abnormalities (n=4, 2%). In univariate models no individual covariate was a strong predictor of toxicity. Only 3 pairs of toxicity/covariate had an AUC > 0.65 [indicating modest predictive ability]: older age predicting increased risk of endocrine abnormalities (OR=1.08 [per year], p=0.06, AUC=0.67), higher baseline WBC predicting increased risk for bleeding (OR=1.26 per 1,000, p=0.36, AUC=0.67), and higher baseline HGB predicting increased risk of neurologic toxicity (OR=1.33 per g/dL, p=0.10, AUC=0.69). As incidence allowed, we evaluate multivariable models. Multivariable models had increased AUC compared to univariate models, but no multivariable model had an AUC larger than 0.70. Conclusion: These findings indicate that with the baseline covariates evaluated, we have a poor ability to predict commonly occurring grade 3 and higher toxicities that occur during the first cycle of 7+3 induction therapy for AML. These findings support the claim that randomization is necessary to compare toxicities between standard and investigational regimens. Moreover, assuming that trial eligibility criteria are often stringent in an attempt to minimize the occurrence of treatment toxicities in study participants, the lack of strong association between individual baseline characteristics and toxicities could be used to argue for less-stringent study inclusion criteria. Support: NIH/NCI grants CA180888 and CA180819 Disclosures Walter: Aptevo Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Amphivena Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Covagen AG: Consultancy, Other: Clinical Trial Support, Research Funding; Seattle Genetics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Pfizer, Inc: Consultancy; Amgen Inc: Other: Clinical Trial Support, Research Funding; Actinium Pharmaceuticals, Inc: Other: Clinical Trial support , Research Funding; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy.

scholarly journals A Phase Ib Clinical Trial of Metformin and Chloroquine in Patients with IDH1-Mutated Solid Tumors

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2474
Author(s):  
Mohammed Khurshed ◽  
Remco J. Molenaar ◽  
Myra E. van Linde ◽  
Ron A. Mathôt ◽  
Eduard A. Struys ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Intrahepatic Cholangiocarcinoma ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Idh1 Mutation ◽  
Resonance Spectroscopy ◽  
Isocitrate Dehydrogenase 1 ◽  
Who Grade ◽  
Phase Ib

Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. These solid IDH1-mutated tumors produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are more vulnerable to disruption of their metabolism. Methods: Patients with IDH1-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma received oral combinational treatment with the antidiabetic drug metformin and the antimalarial drug chloroquine. The primary objective was to determine the occurrence of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD). Radiological and biochemical tumor responses to metformin and chloroquine were investigated using CT/MRI scans and magnetic resonance spectroscopy (MRS) measurements of D-2HG levels in serum. Results: Seventeen patients received study treatment for a median duration of 43 days (range: 7–74 days). Of twelve evaluable patients, 10 patients discontinued study medication because of progressive disease and two patients due to toxicity. None of the patients experienced a DLT. The MTD was determined to be 1500 mg of metformin two times a day and 200 mg of chloroquine once a day. A serum D/L-2HG ratio of ≥4.5 predicted the presence of an IDH1 mutation with a sensitivity of 90% and a specificity of 100%. By utilization of digital droplet PCR on plasma samples, we were able to detect tumor-specific IDH1 hotspot mutations in circulating tumor DNA (ctDNA) in investigated patients. Conclusion: Treatment of advanced IDH1-mutated solid tumors with metformin and chloroquine was well tolerated but did not induce a clinical response in this phase Ib clinical trial.

Cancer clinical trials available in the community setting: A 5-year analysis from 1999–2004

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6056-6056
Author(s):  
J. K. Keller ◽  
J. Bowman ◽  
J. A. Lee ◽  
M. A. Mathiason ◽  
K. A. Frisby ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Cancer Patients ◽  
Community Setting ◽  
Disease Stage ◽  
Cancer Center ◽  
Newly Diagnosed ◽  
Community Based ◽  
Eligibility Criteria ◽  
Major Barrier

6056 Background: Less than 5% of newly diagnosed cancer patients are accrued into clinical trials. In the community setting, the lack of appropriate clinical trials is a major barrier. Our prospective study in 2004 determined that 58% of newly diagnosed adult cancer patients at our community-based cancer center didn’t have a clinical trial available appropriate for their disease stage. Among those with clinical trials, 23% were subsequently found to be ineligible (Go RS, et al. Cancer 2006, in press). However, the availability of clinical trials may vary from year to year. Methods: A retrospective study was conducted to determine what clinical trials were available for newly diagnosed adult cancer patients at our institution from June 1999-July 2004. The study also investigated the proportions of newly diagnosed patients who had a clinical trial available appropriate for type and stage of disease and patients accrued. Results: Over the 5-year period, 207 (82, 87, 99, 102, 117, years 1–5, respectively) trials were available. Most (50.7%) trials were for the following cancers: breast (15.5%), lung (13.5%), head and neck (7.7%), colorectal (7.2%) and lymphoma (6.8%). ECOG (53%), RTOG (26%), and CTSU (9%) provided the majority of the trials. A total of 5,776 new adult cancer patients were seen during this period. Overall, 60% of the patients had a trial available appropriate for type and stage of their cancer, but only 103 (3%) were enrolled. There was a significant upward trend in the proportions of patients with available trials over the years (60.2%, 55.9%, 59.2%, 60.7%, 63.9%, years 1–5, respectively; Mantel-Haenszel P=.008). The proportion of patients with a trial available was highest for prostate (97.3%), lung (90.9%), and breast (73.9%), and lowest for melanoma (17.1%), renal (11.6%), and bladder (7.2%). The majority of patients accrued to trials had the following cancers: breast (32%), lung (17%), lymphoma (9%), colon (7%), and prostate (5%). Conclusions: Nearly half of the newly diagnosed adult patients at our center had no trials available appropriate for type and stage of their cancers. It is likely that if strict clinical trial eligibility criteria were applied, approximately 2/3 of our patients would not be eligible for a clinical trial. No significant financial relationships to disclose.

Phase I dose escalation of ibrutinib and buparlisib in relapsed/refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7544-7544 ◽  
Author(s):  
Connie Lee Batlevi ◽  
Paul A. Hamlin ◽  
Matthew J. Matasar ◽  
Steven M. Horwitz ◽  
John F. Gerecitano ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Serious Adverse Events ◽  
Pi3k Inhibitors ◽  
Grade 3 ◽  
Dose Reductions

7544 Background: In vitro studies of BTK and PI3K inhibitors demonstrate synergy in non-Hodgkin lymphoma (NHL). We embarked on a phase I/Ib investigator-initiated clinical trial evaluating the combination of ibrutinib (BTK inhibitor) and buparlisib (pan-PI3K inhibitor) in relapsed/refractory (R/R) NHL. The completed dose escalation is reported. Methods: Patients (pts) were eligible if they had R/R DLBCL, MCL, or FL with ECOG≤2 and adequate organ function. Ibrutinib and buparlisib were given daily by mouth on a 28-day cycle. Dose reductions were permitted after cycle 1. Tumor response was based on Lugano Classification however CR required both PET resolution and ≥ PR by CT. Results: As of Dec 16, 2016, 13 pts were enrolled and evaluated for toxicity (DLBCL 5, FL 2, MCL 6). Dose levels and DLT per table. Six pts discontinued treatment for disease progression (DLBCL 4, FL 2). Hematologic AE ≥ grade 3 are anemia (2), leukocytosis (2), and leukopenia (4). Relevant non-hematologic AEs of any grade ≥ 20% across all pts were fatigue (77%), diarrhea (62%), anorexia (54%), rash (46%), hyperbilirubinemia (46%), gastric reflux (46%), CMV reactivation (31%), mood change (31%), and hypertension (23%). Most common related grade 3/4 toxicity is rash (N = 3). No grade 5 toxicities noted. Serious adverse events (SAE) include: grade 2 pleural effusion and grade 2 nausea (N = 1), grade 1 fever with hospitalization (N = 1), grade 2 confusion and grade 4 hyponatremia (N = 1) were unrelated to therapy. Responses noted in 13 pts: MCL (N = 6: CR 4, PR 2), FL (N = 2: SD 2), DLBCL (N = 5: SD 1). One CR was a MCL pt with CR after 2 cycles on combination therapy and continues in remission on ibrutinib alone because of buparlisib toxicity. Conclusions: Combination of ibrutinib and buparlisib while generally well tolerated has predicted toxicities of both BTK and PI3K inhibitors. The recommended phase 2 dose is ibrutinib 560 mg and buparlisib 100 mg though dose reductions for tolerability may be needed for long term oral therapies. Promising efficacy is observed in MCL. Clinical trial information: NCT02756247. [Table: see text]

Maximum tumor dimension and tumor volume as prognostic factors in patients with newly diagnosed localized Ewing sarcoma (ES)- a report from the Children’s Oncology Group (COG).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11529-11529
Author(s):  
Leo Mascarenhas ◽  
Allen Buxton ◽  
Steven G. DuBois ◽  
Dian Wang ◽  
Nadia N. Laack ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Prognostic Factors ◽  
Tumor Size ◽  
Tumor Volume ◽  
Cox Model ◽  
Rank Test ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Increased Risk ◽  
Significant Difference

11529 Background: Maximum tumor dimension > 8 cm. and large tumor volume have been reported to be adverse prognostic factors in patients with ES but have not been prospectively evaluated in the context of a phase 3 clinical trial with interval compressed chemotherapy. Methods: COG AEWS1031 (NCT01231906) was a randomized phase 3 clinical trial comparing interval compressed chemotherapy regimens in patients with newly diagnosed localized ES of bone and soft tissue. A correlative objective of AEWS1031 was to evaluate tumor size and volume as prognostic factors. Institution-reported dimensions of the primary tumor from baseline imaging were prospectively collected. For inclusion in this analysis, patients had to have at least 1 tumor dimension reported for tumor size analyses and dimensions in 3 axes for tumor volume analyses. Maximum dimension was dichotomized as less than vs. > / = 8cm. Tumor volume was dichotomized as less than vs. > / = 200 mL. Event-free (EFS) and overall survival (OS) from enrollment were calculated using Kaplan-Meier methods and compared between groups using a two-sided log-rank test. Hazard ratios (HR) and confidence intervals (CI) were calculated using the Cox model. Results: The 5-year EFS and OS of the 629 eligible patients was 78% (95% CI: 75-81%) and 87% (95% CI: 84-90%) respectively and there was no significant difference in both EFS and OS between the randomized interval compressed chemotherapy arms of AEWS1031. 590 of 629 (94%) patients were evaluable for maximum tumor dimension and 307 (52%) had tumors > / = 8 cm. Patients with tumors > / = 8 cm were at significantly increased risk for EFS events (p = 0.016) with estimated 5-year EFS of 73.7% (95% CI: 68.1 vs.78.4%) vs. 82.9% (95% CI 77.7-87.1%) for patients with tumors < 8 cm [HR: 1.53 (1.08-2.17)]. For tumor volume, 586 of 629 patients (93%) were evaluable and 180 (31%) had tumors > / = 200 mL. Patients with tumor volume > / = 200 mL were at significantly increased risk for EFS events (p = 0.003) with estimated 5-year EFS of 70% (95% CI: 62.3-76.4%) vs. 81.6% (95% CI: 77.2-85.2%) for patients with tumors < 200 mL [HR: 1.69 (1.2-2.39)]. Conclusions: Maximum tumor dimension and tumor volume as defined are both prognostic in patients with newly diagnosed localized ES treated with interval compressed chemotherapy. Clinical trial information: NCT01231906 .

Dose escalation and expansion cohort study for DS-8895a in patients with advanced solid tumors.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 99-99 ◽  
Author(s):  
Taroh Satoh ◽  
Kohei Shitara ◽  
Satoru Iwasa ◽  
Kensei Yamaguchi ◽  
Kei Muro ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Japanese Patients ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Igg1 Monoclonal Antibody ◽  
Grade 3 ◽  
Expansion Cohort

99 Background: Erythropoietin-producing hepatocellular receptor A2 (EPHA2) is overexpressed on the cell surface of many tumors and is associated with poor prognosis, suggesting EPHA2 as a target for cancer therapy. DS-8895a is an afucosylated, humanized anti-EPHA2 IgG1 monoclonal antibody with potent cytotoxicity. We report results from a phase I clinical trial to determine safety, tolerability, and pharmacokinetics (PK) of DS-8895a in Japanese patients with advanced solid tumors (NCT02004717). Methods: Step 1 (dose escalation cohort) had patients with advanced solid tumors and comprised of six dose levels (0.1–20 mg/mL, intravenous infusion, every 2 weeks [Q2W]) with a 28-day dose limiting toxicity (DLT) evaluation period. Step 2 (expansion cohort) patients had gastric or esophageal cancer confirmed to be EPHA2 positive by immunohistochemistry. Dose level in Step 2 was determined based on results obtained in Step 1. We evaluated safety, PK, potential biomarkers including circulating NK cells and cytokines, and tumor response. Results: Maximum tolerated dose was not reached in Step 1 (n = 22). DS-8895a was administered at 20 mg/kg Q2W in Step 2 (n = 15). Among 37 patients in the safety analysis set, adverse events (AEs) were reported in 97.3% (64.9% drug-related); 35.1% presented grade ≥ 3 AEs (8.1% drug-related). Dose delay and study discontinuation due to AEs (treatment related: grade 4 platelet decrease, hypoesthesia, hypotension, peripheral coldness, nausea, and vomiting) were observed in one and four patients (20 mg/kg), respectively. Infusion-related reactions occurred in 51.4% of patients resulting in 10 dose interruptions with one discontinuation. Serum inflammatory cytokines were transiently increased 4 h from the end of infusion drug administration. Serum DS-8895a maximum and trough concentrations increased dose-dependently. Biomarkers had no apparent relationship to best overall response. Seven patients in Step 1 achieved stable disease; in Step 2, six patients achieved stable disease and one patient achieved partial response. Conclusions: DS-8895a was safe and well tolerated up to 20 mg/kg. The PK of DS-8895a was dose-dependent as expected. Clinical trial information: NCT02004717.

Phase I study of ECO-4601, a novel Ras pathway inhibitor

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14128-14128 ◽  
Author(s):  
P. Kavan ◽  
D. Melnychuk ◽  
A. Langleben ◽  
S. D. Baker ◽  
A. Bangash ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Dose Escalation ◽  
Mapk Pathway ◽  
Plasma Concentrations ◽  
Antitumor Efficacy ◽  
Tumor Xenograft ◽  
Continuous Exposure ◽  
Grade 3

14128 Background: ECO-4601 is a structurally novel farnesylated dibenzodiazepinone with broad μM in vitro cytotoxic activity, and in vivo antitumor efficacy in rat glioma, hormone-independent human prostate, breast tumor xenograft tumor models. Preclinical data suggest ECO-4601 is a targeted anticancer drug with dual activity: selective binding to the peripheral benzodiazepine receptor (PBR), resulting in apoptosis, and inhibition of the Ras-MAPK pathway. Greatest efficacy was observed with continuous exposure, and a target plasma ECO-4601 efficacy concentration was determined. Preclinical toxicity studies did not demonstrate significant or dangerous side-effects. ECO-4601 is currently in phase I clinical trial testing to determine toxicity, pharmacologic profile and antitumor efficacy. Methods: ECO-4601 is administered as a 2-week continuous i.v. infusion (CIV), followed by 1 week off in repeated 21 day cycles. The trial includes dose- escalation and dose-extension portions, with comprehensive pharmacokinetics (PK) during the first cycle. Dose-escalation consists of increased doses in single pts until grade 3 toxicity is observed during cycle 1 of treatment, with up to five additional pts dosed to confirm dose-limiting toxicity (2/6 pts with grade 3 toxicities). The extension portion includes up to 15 pts at the dose determined in the first portion. Patients with a variety of cancers have been treated, including colorectal (10), ovarian (2), duodenal (1), and glioma (1). Results: ECO-4601 doses of 30, 60, 120, 180, 270, 360, and 480 mg/m2/day were evaluated in 14 patients. The number of cycles ranged from 1 to 8 with 7 pts completing at least 3 cycles of treatment. ECO-4601 is well tolerated and a maximum tolerated dose (MTD) has not been reached. Stable disease was observed in 6 of 7 evaluable pts; 4 colorectal, 1 ovarian, 1 duodenal. Preliminary PK shows steady state concentrations following 24 h CIV, dose proportionality, plasma concentrations above the preclinical efficacy threshold, rapid elimination post-infusion. Conclusions: ECO-4601 is a bifunctional targeting agent, against a novel combination of targets, that is well tolerated and demonstrates evidence of biological activity in an early phase clinical trial. The extension portion is currently ongoing. [Table: see text]

Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 490-490 ◽  
Author(s):  
Fatima A. Rangwala ◽  
Johanna C. Bendell ◽  
Mark Kozloff ◽  
Christy Arrowood ◽  
Jennifer Meadows ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Rectovaginal Fistula ◽  
Dose Intensity ◽  
Advanced Solid Tumors ◽  
Increased Risk ◽  
Level 1 ◽  
Grade 3

490 Background: Everolimus (E), an oral rapamycin analogue, is a potent mTOR inhibitor. Combined inhibition of VEGF and mTOR pathways may increase anti-angiogenic and anti-tumor activity. We evaluated E in combination with capecitabine (C), oxaliplatin (O), and bevacizumab (B) in a phase I dose escalation study. Methods: Eligible patients (pts) had advanced solid tumors, adequate organ function and no increased risk for class-related toxicities. B and O were given intravenously; C and E were orally administered. Cycle length was 21 days. Doses for level 1: C 850 mg/m2 on days 1-14; O 130 mg/m2 on day one; B 7.5 mg/kg on day one; and E 5 mg three times a week. Doses for level -1: C 680 mg/m2, O100mg/m2. An intermediate dose level (-1b) of E escalated to 5 mg five times weekly was added to maximize dose intensity. Dose limiting toxicity (DLT) was assessed in cycle 1. Concomitant administration of CYP3A4 substrates, inhibitors or inducers was prohibited. Results: Dose escalation is complete with 27 pts evaluable for toxicity and 24 evaluable for efficacy. Two DLTs (grade 2 intolerable fatigue, anorexia, vomiting and grade 3 diarrhea) were observed in 6 pts in cohort 1. No DLTs were observed in cohort -1; one DLT (rectovaginal fistula) was observed in the -1b cohort. Possible grade ≥3 treatment-related adverse events any time on study (n=1 except as indicated) included diarrhea (n=2), intestinal perforation/fistula, rectovaginal fistula, hypertriglyceridemia (n=3), hyperglycemia, hypoalbuminemia, hyponatremia, peripheral neuropathy, neutropenia (n=2), lymphopenia, thrombocytopenia, hypertension (n=3), deep vein thrombosis, and arterial thrombosis. Adverse events were consistent with known class-related toxicities. For efficacy, 10 pts had a partial response (PR); 10 had stable disease as best response. Of 13 pts with chemorefractory metastatic colorectal cancer (mCRC), 5 had a PR. Of 8 pts with chemonaive mCRC, 5 had a PR. Conclusions: E in combination with full dose C, O and B was associated with unacceptable toxicity, primarily GI toxicity. E at 5mg five times weekly, C at 680 mg/m2 on days 1-14, O at 100 mg/m2 and B at 7.5 mg/kg on day one appears well tolerated. Activity was noted in chemorefractory and chemonaive mCRC patients.

Dasatinib In Children and Adolescents with Relapsed or Refractory Leukemia: Results of the CA180018 Phase 1 Dose-Escalation Study of the Innovative Therapies for Children with Cancer (ITCC) Consortium

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2265-2265 ◽  
Author(s):  
C. Michel Zwaan ◽  
Carmelo Rizzari ◽  
Francoise Mechinaud ◽  
Donna L Lancaster ◽  
Pamela R. Kearns ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Maximum Concentration ◽  
Phase 1 ◽  
Molecular Response ◽  
Cell Transplant ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Dose Escalation Study ◽  
Safety And Efficacy ◽  
Grade 3

Abstract Abstract 2265 Background: Pediatric relapsed/refractory leukemia portends a poor prognosis and more effective therapies are urgently needed. Dasatinib is a potent oral BCR-ABL inhibitor approved for treating adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resistant or intolerant to imatinib. Dasatinib also has activity against SRC-family kinases and KIT. A phase 3 trial of dasatinib vs imatinib in adults with newly diagnosed with CML in chronic phase (CP) showed superior efficacy of dasatinib with good tolerability (Kantarjian et al. NEJM 2010:362:2260). Methods: The CA180018 trial is a component of a European Medicines Agency-approved comprehensive Pediatric Investigation Plan for dasatinib aimed at improving outcomes in pediatric leukemias. This trial is being conducted via the ITCC consortium in 7 countries (15 centers) as a stratified phase 1 dose-escalation study. The primary aim is to establish a safe and effective phase 2 dose of dasatinib in children/adolescents with subtypes of relapsed/refractory leukemia. Secondary objectives include safety, pharmacokinetics (PK), and rates of hematologic, cytogenetic, and molecular response (cytogenetic/molecular responses in Ph+ only). Patients (pts) were stratified into 3 disease strata: Stratum 1, imatinib-resistant/intolerant Ph+ CML-CP; Stratum 2/3, advanced CML resistant to imatinib or Ph+ ALL relapsed/refractory after imatinib or Ph+ AML in ≥2nd relapse (original strata merged by protocol amendment due to slow enrolment); and Stratum 4, ≥2nd relapse of Ph– ALL or AML. Starting doses were 60, 80, 100, and 120 mg/m2 once daily, with dose escalations based on safety and efficacy. Intrapatient dose escalation was allowed for lack of response. Results: The study opened in March 2006 and closed to accrual in October 2009. 58 pts have been treated, of which 50 (86%) completed therapy by data cut-off of May 2010. No pts with Ph+ AML were enrolled. All pts had prior therapy, including imatinib in 59% (all Ph+ pts), anagrelide or hydroxyurea in 22%, interferon in 3%, other chemotherapy in 69%, radiotherapy in 43%, and stem cell transplant in 50%. Median age (yrs) was 11, including 2 pts (3%) aged <2, 32 (55%) aged 2–11, 23 (40%) aged 12–18, and 1 (2%) aged >18. 39 pts (67%) were male. No pt with Ph– AML had a KIT mutation. Median durations of therapy (range) were: Stratum 1, 11.3 mos (2.3–47.9); Stratum 2/3, 3.0 mos (0.5–24.6); and Stratum 4, 1.1 mos (<0.1–3.4). Dasatinib up to 120 mg/m2, including long-term therapy, was well tolerated. Common drug-related toxicities (≥10%) were: nausea (grade 1/2 in 16 pts [28%], grade 3 in 1 [2%]); headache (grade 1/2 in 11 [19%], grade 3 in 2 [3%]); diarrhea (grade 1/2 in 12 [21%]); vomiting (grade 1/2 in 9 [16%], grade 3 in 1 [2%]); rash (grade 1/2 in 9 [16%]); and pain in extremity (grade 1/2 in 6 [10%]). Pleural effusion occurred in 2 pts (3%) at grade 1 and 1 pt (2%) at grade 3. Two dose-limiting toxicities were seen in Stratum 4: grade 4 anaphylaxis 5 h after first dose (60 mg/m2) and grade 3 upper GI bleed on Day 6 (120 mg/m2) in a pt with platelet count of 16×109/L. Maximum tolerated dose has not been established. PK parameters, analyzed in 52 pts to date, showed high interpatient and intrapatient variability. Dasatinib was rapidly absorbed with median time to maximum concentration of 1.0 h irrespective of dose. Mean half-life ranged from 2.1–3.6 h. With dasatinib 60, 80, 100, or 120 mg/m2, area under the curve was 374, 530, 424, and 606 ng.h/mL and maximum concentration was 113, 138, 114, and 183 ng/mL, respectively. Treatment responses were seen in Ph+ pts who received dasatinib 60 or 80 mg/m2. In Stratum 1 (CML-CP; n=17), rates were complete hematologic response (HR) in 16 (94%), complete cytogenetic response (CCyR) in 14 (82%), major molecular response (MMR) in 6 (35%), and complete molecular response in 4 (24%). In Stratum 2/3 (advanced CML/Ph+ ALL; n=17), rates were major HR in 10 (59%), CCyR in 12 (71%), and MMR in 0/2 pts with advanced CML assessed to date. No pt in Stratum 4 responded (Ph– ALL/AML; n=24). Final data will be presented. Conclusions: This trial shows the safety and efficacy of dasatinib in pediatric pts with Ph+ leukemias and supports the feasibility of evaluating new agents in children with rare malignancies through cooperative group efforts. A phase 2 study is underway to further evaluate dasatinib in children/adolescents with Ph+ leukemias, including newly diagnosed CML. Disclosures: Zwaan: Bristol-Myers Squibb: Consultancy. Off Label Use: Dasatinib treatment of pediatric leukemias. Rosenberg: Bristol-Myers Squibb: Employment, Equity Ownership. Herdlicka: Bristol-Myers Squibb: Employment. Derreumaux: Bristol-Myers Squibb: Employment. Agrawal: Bristol-Myers Squibb: Employment.

A Phase I/II Trial of Combination Gemcitabine and Bortezomib (VELCADE®) for Relapsed/Refractory T-Cell Non-Hodgkin Lymphoma (NHL) and Aggressive B-Cell NHL

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1646-1646
Author(s):  
Andrew M. Evens ◽  
Steven T. Rosen ◽  
Leo I. Gordon ◽  
Irene Helenowski ◽  
Justin Kline ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Phase I ◽  
B Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Treatment Cycle ◽  
Treatment Schedule ◽  
Dosing Schedule ◽  
Grade 3

Abstract Abstract 1646 Background: NF-κB has been shown to be deregulated in B-NHL and T-NHL subtypes. The proteasome inhibitor, bortezomib, has the capacity to reverse the downstream consequences of NF-κB, while gemcitabine has documented single-agent activity in relapsed/refractory NHL. Further, in vitro and murine xenograft tumor models have demonstrated synergy between these two agents. Based on these data, and the continued unmet clinical need for patients with relapsed/refractory aggressive NHL either ineligible for or relapsed after stem cell transplant (SCT), we conducted a phase I/II trial utilizing this novel combination. Methods: This was a phase I/II investigator-initiated clinical trial conducted through two centers. The phase I design was a classic 3+3 with dose escalation of bortezomib (1.3 mg/m2 to 1.6 mg/m2 given day (D) 1 and D8) with static gemcitabine dosing (800 mg/m2 D1 and D8) given on q 21 day cycles. The definition of dose limiting toxicity (DLT) was: a) grade 3 or 4 non-hematologic toxicity (other than grade 3 nausea or vomiting); b) grade 4 vomiting despite maximal anti-emetic support; c) grade 4 neutropenia on D1 of a treatment cycle (despite growth factor support); and d) grade 4 thrombocytopenia on D1 of a treatment cycle. Following completion of bortezomib escalation, a planned phase II expansion of the study was planned. The null hypothesis was that the true success was less than or equal to 15% and the alternate hypothesis was that the true success was 40% or higher; type I error of 5% and a power of 80% was assumed. Results: From April 2006 to December 2010, we enrolled 32 relapsed/refractory NHL pts onto this phase I/II clinical trial. Sixteen pts had T-NHL (n=12 peripheral T-NHL NOS and n=1 each with angioimmunoblastic T-NHL, NK-/T-NHL, transformed large cell [from pre-existing cutaneous T-cell], and hepatosplenic) and 16 had B-NHL (all relapsed/refractory DLBCL). There were 16 women and 16 men with a median age of 61 years (range, 37–85 years). The median ECOG performance status was 1 (range, 0–2), median prior therapies were 2.5 (range, 1–5), while 35% had failed prior autologous SCT. During the initial phase I dose escalation, 2 DLTs were noted (grade 3 hypertension and grade 3 elevation of liver function tests), while a maximally tolerated dose was not identified. However, among the first 18 pts treated on the D1+D8 (q21 day) dosing schedule, 67% experienced grade 3/4 neutropenia and/or grade 3/4 thrombocytopenia, primarily on D8 of treatment cycles. These recurrent D8 cytopenias resulted in repeated treatment delay(s). The median number of cycles delivered for these 18 pts were 1.0 (due to hematotoxicity), which was associated with a low (59%) median normalized dose-intensity. Thus, in early 2009, the clinical trial was amended instituting a modified treatment schedule of gemcitabine 800 mg/m2 and bortezomib 1.6 mg/m2 to both be administered on D1 and D15 of a 28-day schedule for an additional 22 patients. Treatment-related toxicity was markedly reduced using this modified treatment schedule; only one grade 3 event each of anemia and thrombocytopenia were recorded. However, after 14 pts had accrued to the modified treatment schedule, efficacy data were analyzed by the Northwestern University Data Monitoring Committee (DMC). Among all 32 patients, the ORR was 16% (complete remission (CR) 13%). Further, the ORR for all B-NHL pts was 6% (no CR) and 25% for T-NHL (19% CR). On the modified D1+D15 treatment schedule, the ORR for B-NHL was 0% (0/8); while among T-NHL, the ORR was 50% (3/6) with each of these latter pts remaining in continued remission at 29+, 26+, and 19+ months. Nevertheless, an analysis performed by the DMC for the overall study conduct recommended premature study closure; thus the final planned 8 pts did not enroll. Conclusions: We determined in this phase I/II study for pts with relapsed/refractory, aggressive T-NHL and B-NHL that combined bortezomib/gemcitabine using a dosing schedule of D1+8 q21 days was not tolerated and is not recommended for further study. Modification of bortezomib/gemcitabine dosing to D1+15 q28 days was tolerated markedly better, allowing consistent treatment delivery. Altogether, clinical efficacy of gemcitabine plus bortezomib in aggressive B-NHL was low (with either schedule), while there was a potential signal of activity with durable responses in a small number of pts in the T-NHL population utilizing the modified treatment schedule. Disclosures: Evens: Millennium: Research Funding, advisory board. Off Label Use: Velcade in T-cell and aggressive (non-MCL) B-cell NHL. Winter:Millennium: Research Funding. Smith:Millennium: Research Funding.

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