Dataset Information

Phase Ib Study of TNO155 in Combination With Spartalizumab or Ribociclib in Selected Malignancies

ABSTRACT: This study is a Phase Ib, multi-center, open-label study of TNO155 in combination with spartalizumab or ribociclib with a dose escalation part followed by a dose expansion part in adult subjects with advanced solid tumors. These two treatment arms will enroll subjects in parallel to characterize the safety, tolerability, PK, PD and preliminary antitumor activity. The study treatment will be administered until the subject experiences unacceptable toxicity, progressive disease, and/or has treatment discontinued at the discretion of the Investigator or the subject, or due to withdrawal of consent.

DISEASE(S): Squamous Cell Carcinoma Of Head And Neck,Carcinoma,Esophageal Scc,Colorectal Cancer,Carcinoma, Non-small-cell Lung,Head And Neck Squamous Cell Carcinoma,Nsclc,hnscc,esophagus Scc,gist,crc,Non-small Cell Lung Carcinoma,Esophageal Squamous Cell Carcinoma,Gastrointestinal Stromal Tumors

PROVIDER: 2309436 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

ACCESS DATA

Similar Datasets

Project description:This pharmacogenomic study focused on the response of patients with MDD to an 8-week course of treatment with citalopram or escitalopram. Briefly, clinical assessments and research assessments were performed at each study visit as summarized in Table 1. Many patients continued on antidepressant medication after the 8 week study. Table 1: Study timeline and patient contacts. <table border="1"> <tr> <th>Week</th> <th>Consent/Med Hx</th> <th>Write Rx</th> <th>SI Qx</th> <th>SCID</th> <th>HRS-D17</th> <th>QIDSC16</th> <th>CGI-I</th> </tr> <tr> <td>0</td> <td>SC</td> <td>RC</td> <td>RC</td> <td>SC</td> <td>SC</td> <td>SC</td> <td></td> </tr> <tr> <td>4</td> <td></td> <td>RC</td> <td>RC</td> <td></td> <td>SC</td> <td>SC</td> <td>RC</td> </tr> <tr> <td>8</td> <td></td> <td>RC</td> <td>RC</td> <td></td> <td>SC</td> <td>SC</td> <td>RC</td> </tr> </table> HRS-D17=Hamilton Rating Scale for Depression, QIDS-C16=Quick Inventory of Depressive Symptomatology, CGI-I=Clinical Global Impression-Improvement, SCID=Structured Clinical Interview for DSM-IV, SC=Study Coordinator, RC=Research Clinician. Enrollment and baseline assessment. Upon initial intake, the Study Coordinator (SC) obtained informed consent as well as clinical and demographic information, including history of bone marrow or liver transplant or blood transfusion within the previous 6 weeks, and prior history of treatment during the current major depressive episode. The SC completed the Structured Clinical Interview for DSM-IV (SCID), the HRS-D17 (17-item Hamilton Rating Scale for Depression) and the QIDS-C16 (Quick Inventory of Depressive Symptomatology) and reviewed the inclusion/exclusion criteria. After review with the Research Clinician (RC) and when appropriate, after a negative pregnancy test, the SC invited the subject to participate in the study if entry criteria were met. If the subject agreed, he/she received treatment according to the study protocol. Treatment schedule. Participants selected for inclusion in the study were seen at weeks 0, 4, and 8. The appropriate treatment antidepressant (citalopram or escitalopram) was determined following discussion between the patient and RC concerning medical, financial, and insurance considerations. The study medication citalopram was given in tablet or liquid form, depending on the patient's need. A fixed-flexible dose schedule was employed with the possibility of a dose escalation. In particular, the initial dose of citalopram was 20 mg and escitalopram was 10 mg. This dose was increased to 40 mg and 20 mg, respectively, after 4 weeks if the subject had a score of >/= 6 on the QIDS-C16 and the RC concluded that the subject could tolerate the increase. If necessary, dose was reduced at the discretion of the RC. The importance of medication compliance was discussed with the subject, and subjects were asked to bring in the medication at each visit for the purpose of counting remaining pills to assess compliance. Participants may have had an abbreviated course of therapy if they were clearly intolerant of the drug or failed to respond to a 40 mg dose of citalopram or a 20 mg dose of escitalopram. They then received standard treatment from a primary physician or psychiatrist with different medications and/or therapeutic modalities (e.g. psychotherapy). Special attention was given to subjects with suicidal ideation. Those subjects were offered additional appointments as needed to ensure their safety. Participants were also contacted by telephone at week 1 and week 2 by the Clinical Nurse Specialist (CNS) or other study personnel to ensure medication compliance and patient safety. The CNS was supervised by the study psychiatrist and principal investigator and deferred to the physician's judgment as needed. The SC was trained to notify the RC at the time of the clinical visits or the phone interviews if the subject endorsed any suicidal ideation or plans. For those subjects who were unable to attend the follow-up visits as scheduled, the patient was contacted by phone to complete the HRS-D17/QIDS-C16. The participant was also asked to return to the clinic to complete a final blood draw for the study. Adjunctive and concurrent medications. Adjunctive treatments were those used to manage transient associated symptoms (e.g., insomnia) or transient or longer-term medication side effects (e.g., sexual dysfunction). Adjunctive treatments that were not used to treat depression were allowed during the study. However, drugs in the exclusion criteria for this study were not used as adjunctive therapies. Subjects were allowed to participate in the study while receiving concurrent medications for general medical conditions as long as there was no contraindication to use while taking citalopram or escitalopram. Drug efficacy phenotype evaluation. The change in QIDS-C16 score and change in HRS-D17 score were used as the major research outcome measures to assess drug response. At each clinical research visit, the RC also completed the Clinician Global Impression of Improvement (CGI-I) scale. For the primary genome-wide association analyses, dichotomous outcome variables, remission and response, were defined based on the QIDS-C16 last visit score. Remission was defined as a QIDS-C16 score of 5 or less, while response was defined as at least a 50% reduction in the QIDS-C16 score from baseline. Specimen collection. Specimen collections were obtained by the General Clinical Research Center (GCRC) at St. Mary's Hospital (SMH). Subjects had blood drawn on an outpatient basis at GCRC-SMH on three separate occasions - baseline (0), week 4 and week 8 visits. Prior to sample collection, date and time of last dose of study medication was gathered at the 4 and 8 week visits. For those patients who were unable to complete the regularly scheduled visits, a dismissal blood draw was requested. GCRC then shipped samples to Mayo Clinic's Biospecimens Accessioning and Processing Lab. Genotyping and biomarker assays. DNA from 529 patients was genotyped by the RIKEN Center for Genomic Medicine (Yokohama, Japan) using Illumina Human610-Quad BeadChips (Illumina, San Diego, CA). The study also included the determination of plasma drug levels at weeks 4 and 8, and metabolite levels at baseline and weeks 4 and 8 for a subset of subjects. The primary genome-wide association study based on these data, which includes a summary of the protocol, subject description, selection of subjects for genetic analyses, and definitions of clinical outcomes, was published in the Pharmacogenomics Journal (<a href="http://www.ncbi.nlm.nih.gov/pubmed/22907730">Ji et al., 2012</a>).

Project description:LGL leukemia can be divided into three subsets including the following: αβ or γδT-LGL and NK-LGL leukemia. All three subtypes will be enrolled using a two-stage design. The primary endpoint of the study is assessment of overall clinical response. Correlative laboratory studies will be performed aimed at determining the mechanism of response to treatment. Thirteen participants will be accrued in the first stage at a dose of 300 mg BID administered intermittently every other week (i.e., 7 days on and 7 days off). If there are two or more responders, the protocol will be extended to a second stage of the study and accrual will be extended to 25 evaluable participants. Allowing for 10% rate of ineligibility due to unexpected events and dropout, we will accrue 14 patients in the first stage and 27 patients in total. Participants that withdraw from the study for reason unrelated to toxicity, will be replaced. There are two potential stopping rules for toxicity. If 3 or more participants out of the 13 enrolled in the first stage experiences grade IV neurotoxicity, the study will be stopped due to excessive toxicity. Dose reductions have been incorporated for hematologic toxicity. Treatment of T and NK LGL leukemia with immunosuppressive agents such as low-dose methotrexate generally require from four to six months for a clinical response and sometimes much longer. Therefore, in participants who show clinical improvement with less than grade three toxicity, tipifarnib treatment will be continued for as many as four additional months (12 months total). After the first 8 months, response will be assessed. The protocol treatment will be discontinued in participants with progression of disease. A long-term follow up will be performed for five years in patients that receive a complete clinical response. The long-term follow up will consist of vital signs, weight, CBCs, serum chemistries, and physical examination at six month intervals.

Project description:Purpose: Decitabine is a deoxycytidine nucleoside derivative inhibitor of DNA-methyltransferases indicated for treatment of myelodysplastic syndrome (MDS). Laboratory evidence shows that pretreatment of AML cell lines can sensitize leukemia cells to chemotherapy and inhibit clonogenic potential. We conducted a randomized study of decitabine when used as priming before standard induction therapy in children with newly diagnosed acute myelogenous leukemia (AML) to evaluate the safety, pharmacokinetics, and any potential early efficacy signal. Exploratory analyses of genomic methylation and RNA expression patterns and minimal residual disease (MRD) were included to elucidate possible biological mechanisms. Methods: This multicenter, randomized, two-arm, open-label study enrolled children ages 1-16 with newly diagnosed de novo AML to either Arm A: daunorubicin, cytarabine, etoposide preceded by a 5-day course of decitabine (experimental arm) or Arm B: daunorubicin, cytarabine, etoposide (control). Following completion of induction therapy, subsequent post-induction treatment was given at the treating physician’s discretion. Patients were monitored for adverse events and samples were collected for PK/PD and biologic analyses. Results: Twenty patients, ages 1-16 years (median 9.4 yrs in both Arms) were treated (10 per Arm). Eighteen of 20 enrolled subjects completed the prescribed treatment. All subjects experienced neutropenia and thrombocytopenia as is expected during AML induction chemotherapy. The most common grade 3 and 4 non-hematologic adverse events observed were caecitis, 2 (20%) subjects in Arm A and 0 (0%) subjects in Arm B; decreased appetite, 3 (30%) subjects in Arm A and 0 (0%) subjects in Arm B; and hypophosphatemia, 2 (20%) subjects in Arm A and 0 (0%) subjects in arm B. One subject in Arm A had appendicitis and colon perforation on Day 6 that led to study discontinuation; the cause was later determined to have been leukemic infiltrate of the bowel wall. Two subjects died (both in Arm A), one of necrotic bowel, pseudomonas sepsis and multisystem organ failure 6 months after study participation and one patient 5 months following study treatment from multisystem organ failure as a complication of stem cell transplant. Plasma concentrations of decitabine showed PK values (mean+SD) of Cmax, 281+113 ng/mL, AUC0-∞, 198+65.3 ng*h/mL, CL, 156+94.6 L/h, Vdss 109+70 L, t1/2 0.48+0.060 h, and median tmax 0.93 h. Overall CR/CRi by morphology was similar between the two treatment arms (92% for the control arm and 100% for the experimental arm). MRD at Day 30 post induction therapy was lower in the control group compared to the decitabine group (67% vs 85% MRD-negative). Changes in DNA epigenetic and RNA expression patterns demonstrated distinct differences involving selective cellular pathways between the two groups of patients comparing diagnostic to day 30 bone marrow samples. Conclusions: This first-in-pediatric trial of epigenetic priming in patients with newly diagnosed AML demonstrates that decitabine pre-treatment followed by standard combination chemotherapy is well tolerated in children with newly diagnosed AML. Morphologic complete responses were similar in both treatment arms. MRD at Day 30 following induction therapy suggests a deeper remission in patients receiving decitabine. No differences were observed between treatment arms in hematologic toxicities although decitabine-treated patients were noted to have more gastrointestinal toxicities, anorexia and hypophosphatemia. Decitabine PK parameters in children were consistent with known adult PK profiles. Molecular changes associated with decitabine pretreatment may be important in the sensitization of clonogenic AML cells. Pre-treatment with decitabine may represent a therapeutic option for use in pediatric AML, when epigenetic modification is a desired focus for treatment.

Dataset Information

Phase Ib Study of TNO155 in Combination With Spartalizumab or Ribociclib in Selected Malignancies

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure