Lenalidomide and irinotecan in adults with recurrent malignant gliomas: Phase I results of the phase I/II trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2036-2036
Author(s):  
Vinay K. Puduvalli ◽  
Morris D. Groves ◽  
Mark R. Gilbert ◽  
Kenneth R. Hess ◽  
Sanghee Kang ◽  
...  
Keyword(s):  
Phase I ◽  
Treatment Options ◽  
Malignant Gliomas ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Who Grade ◽  
Grade 3 ◽  
Thalidomide Analogue ◽  
Irinotecan Dose

2036 Background: Patients with recurrent malignant gliomas have limited treatment options. We previously reported promising results using 6 month progression free survival [PFS6] endpoint combining irinotecan and thalidomide compared to historical controls. In this study, we tested the tolerability and efficacy of Irinotecan combined with Lenalidomide, a more potent thalidomide analogue with unique antiangiogenic and immunomodulatory properties. Methods: This phase I portion of the phase I/II study aimed to determine the maximum tolerated doses (MTD) of irinotecan and lenalidomide. Eligible patients were adults (>=18 y) with recurrent WHO Grade 3 or 4 gliomas who were not on EIAED, had failed prior radiation therapy, had a KPS>=60, had adequate marrow, renal and hepatic organ function, no major medical illnesses and no other concurrent malignancies. Each cycle was designated as 4 weeks in duration. Results: Two of the 4 patients enrolled at the starting dose level of Lenalidomide 10 mg/day on days 1-21 and irinotecan 200 mg/m2 q2 weeks developed rash as dose limiting toxicity (DLT). The trial was restarted with no change in irinotecan dose but with a lowered Lenalidomide dose of 7.5 mg/day for cycle 1 with escalation to 10 mg/day for cycle 2 and beyond. Of 3 eligible patients enrolled, no DLTs were noted even after cycle 2. The dose was hence escalated to Lenalidomide 10 mg/day with unchanged irinotecan dose. Only 1/6 patients experienced a DLT (pulmonary embolism); however, it was noted that 4/6 patients required dose reduction of irinotecan to 150 mg/m2 after cycle 1. One patient died during cycle 2 of unknown causes (autopsy declined) without reports of preceding toxicities. Non DLT toxicities included neutropenia, leukopenia, hypokalemia, diarrhea, fatigue and nausea/vomiting. Lenalidomide pharmacokinetic data, obtained by serial blood draws initially after one dose of the drug on day 0 and subsequently after irinotecan and lenalidomide dose on day 1 to examine drug interactions, will be presented. Conclusions: Based on these results, the maximum tolerated dose was Lenalidomide 10 mg/day on days 1-21 and irinotecan 150 mg/m2 q 2 weeks every 28 days which will be used in the phase II study that will open shortly.

scholarly journals ACTR-01. PHASE I/II STUDY OF TEMOZOLOMIDE PLUS NIMUSTINE CHEMOTHERAPY FOR RECURRENT MALIGNANT GLIOMAS: KYOTO NEURO-ONCOLOGY GROUP

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi12-vi12
Author(s):  
Tomokazu Aoki ◽  
Yoshiki Arakawa ◽  
Tetsuya Ueba ◽  
Masashi Oda ◽  
Namiko Nishida ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Malignant Gliomas ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Free Survival ◽  
Grade 3 ◽  
Experienced Grade

Abstract The objective of this phase I/II study was to examine the efficacy and toxicity profile of temozolomide (TMZ) plus nimustine (ACNU). Patients who had received a standard radiotherapy with one or two previous chemoregimens were enrolled. In phase I, the maximum-tolerated dose (MTD) by TMZ (150 mg/m2/day) (Day 1–5) plus various doses of ACNU (30, 35, 40, 45 mg/m2/day) (Day 15) per 4 weeks was defined on a standard 3 + 3 design. In phase II, these therapeutic activity and safety of this regimen were evaluated. Forty-nine eligible patients were enrolled. The median age was 50 years-old. Eighty percent had a KPS of 70–100. Histologies were glioblastoma (73%), anaplastic astrocytoma (22%), anaplastic oligodendroglioma (4%). In phase I, 15 patients were treated at four cohorts by TMZ plus ACNU. MTD was TMZ (150 mg/m2) plus ACNU (40 mg/m2). In phase II, 40 patients were treated at the dose of cohort 3 (MTD). Thirty-five percent of patients experienced grade 3 or 4 toxicities, mainly hematologic. The overall response rate was 11% (4/37). Sixty-eight percent (25/37) had stable disease. Twenty-two percent (8/37) showed progression. Progression-free survival (PFS) rates at 6 and 12 months were 24% (95% CI, 12–35%) and 8% (95% CI, 4–15%). Median PFS was 13 months (95% CI, 9.2–17.2 months). Overall survival (OS) at 6 and 12 were 78% (95% CI, 67–89%) and 49% (95% CI, 33–57%). Median OS was 11.8 months (95% CI, 8.2–14.5 months). This phase I/II study showed a moderate toxicity in hematology and may has a promising efficacy in OS, without inferiority in PFS.

scholarly journals CTNI-32. PHASE I/II STUDY OF TEMOZOLOMIDE PLUS NIMUSTINE CHEMOTHERAPY FOR RECURRENT MALIGNANT GLIOMAS: KYOTO NEURO-ONCOLOGY GROUP

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii49-ii50
Author(s):  
Tomokazu Aoki ◽  
Yoshiki Arakawa ◽  
Tetsuya Ueba ◽  
Masashi Oda ◽  
Namiko Nishida ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Malignant Gliomas ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Free Survival ◽  
Grade 3 ◽  
Experienced Grade

Abstract The objective of this phase I/II study was to examine the efficacy and toxicity profile of temozolomide (TMZ) plus nimustine (ACNU). Patients who had received a standard radiotherapy with one or two previous chemo-regimens were enrolled. In phase I, the maximum-tolerated dose (MTD) by TMZ (150 mg/m2/day) (Day 1–5) plus various doses of ACNU (30, 35, 40, 45 mg/m2/day) (Day 15) per 4 weeks was defined on a standard 3 + 3 design. In phase II, these therapeutic activity and safety of this regimen were evaluated. Forty-nine eligible patients were enrolled. The median age was 50 years-old. Eighty percent had a KPS of 70–100. Histologies were glioblastoma (73%), anaplastic astrocytoma (22%), anaplastic oligodendroglioma (4%). In phase I, 15 patients were treated at four cohorts by TMZ plus ACNU. MTD was TMZ (150 mg/m2) plus ACNU (40 mg/m2). In phase II, 40 patients were treated at the dose of cohort 3 (MTD). Thirty-five percent of patients experienced grade 3 or 4 toxicities, mainly hematologic. The overall response rate was 11% (4/37). Sixty-eight percent (25/37) had stable disease. Twenty-two percent (8/37) showed progression. Progression-free survival (PFS) rates at 6 and 12 months were 24% (95% CI, 12–35%) and 8% (95% CI, 4–15%). Median PFS was 13 months (95% CI, 9.2–17.2 months). Overall survival (OS) at 6 and 12 were 78% (95% CI, 67–89%) and 49% (95% CI, 33–57%). Median OS was 11.8 months (95% CI, 8.2–14.5 months). This phase I/II study showed a moderate toxicity in hematology and may has a promising efficacy in OS, without inferiority in PFS.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1723-1723
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Peter Anglin ◽  
Christine Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Oral Cyclophosphamide ◽  
Varicella Zoster ◽  
Refractory Multiple Myeloma ◽  
Grade 3 ◽  
Dose Levels

Abstract Oral cyclophosphamide and prednisone is a convenient regimen in relapsed and refractory multiple myeloma (MM), with a partial response (PR) rate of 40% and median progression-free survival of 19 months in our retrospective analysis of patients in first or second relapse after autologous stem cell transplantation (ASCT) (Trieu Y, et al, Mayo Clin Proc2005; 80: 1582). We sought to enhance the efficacy of this regimen by adding oral lenalidomide (Revlimid®), a potent anti-myeloma agent, in a phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15, lenalidomide on days 1–21, and prednisone 100 mg every other day in a 28-day cycle. ASA 81 mg/day was given to all patients (pts) as prophylaxis for DVT. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2008, 15 pts with relapsed/refractory MM were entered onto study. Median age was 60 (45–78) years and 60% were male. Immunoglobulin subtype was IgGκ:λ in 10:1; IgA κ:λ in 2:1 and κ light chain in 1. Median number of prior regimens was 2 (1–3) and 14 had undergone previous ASCT, including double transplants in 2 pts. Prior therapy also included thalidomide in 3 (20%) and bortezomib in 6 (40%). FISH cytogenetics were available in 9, but none had 13q deletion, t(4;14) or p53 deletion. At the time of protocol entry, median β2-microglobulin level was 222 (92–325) nm/L, albumin 38 (35–46) g/L, creatinine 78 (50–100) μmol/L, platelet count 230 (93–318) x 109/L and ANC 2.5 (1.9–9.0) x 109/L. Protocol treatment is summarized in Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 9 2 3 150 25 100 6 3 6 300 25 100 4 3 (expanded) 3 300 25 100 1 Dose limiting toxicity was not observed during cycle 1 at any of the dose levels and the maximum tolerated dose of this regimen has not yet been reached at the highest dose level planned; all pts remain on active therapy. Grade 3/4 thrombocytopenia was seen in 1 pt (cohort 2) and neutropenia in 4 pts (1 in cohort 1, 1 in cohort 2 and 2 in cohort 3) and were managed with dose reduction and/or growth factor support. No episodes of febrile neutropenia occurred in any pt. Only 1 pt experienced varicella zoster; routine antiviral prophylaxis was not used. Other grade 3/4 non-hematologic toxicities were uncommon and included abdominal pain/bacteremia in 1 pt in cohort 1, hypokalemia in 1 pt in cohort 2, and DVT in 1 pt in cohort 3. Mild grade 1/2 constipation (47%), muscle cramps (33%) and fatigue (33%) were also noted. To date, best response includes the following: dose level 1 (1 near complete remission [nCR], 2 PR); dose level 2 (3 PR); dose level 3 (4 PR, 2 minimal response [MR]); expanded cohort 3 (1 MR, 2 too early). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28-day cycle with minimal toxicity; 2) the overall response rate (nCR + PR + MR) in 13 evaluable pts to date is 87%; 3) no pts have progressed in this preliminary analysis; 4) longer follow-up is required to assess the long-term efficacy of this regimen.

First line treatment of HER-2/neu positive advanced breast cancer patients with liposomal doxorubicin (Myocet), docetaxel and trastuzumab. A phase I-II study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10744-10744 ◽  
Author(s):  
D. Amadori ◽  
G. Gasparini ◽  
M. O. Vannozzi ◽  
C. Milandri ◽  
P. Serra ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Dose Level ◽  
Liposomal Doxorubicin ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Treatment Schedule ◽  
Weekly Dose ◽  
Who Grade ◽  
Her 2

10744 Background: Our preclinical data showed synergic effect of Adriamicyn followed by Taxotere in BC cell lines. The combination of anthracyclines, taxanes and trastuzumab could potentially obtain a high number of objective responses and a consistent impact on the time to progression and on the overall survival. The aim of this phase I-II study was to assess the maximum tolerated dose (MTD) of liposomal doxorubicin (Myocet-M) and Taxotere (T) in combination with Herceptin (H). A reduction of cardiotoxicity risk without reducing chemotherapy activity was supposed. Methods: Locally advanced or metastatic her-2/neu positive BC patients (pts) with LVEF ≥ 60% were enrolled in an open, single arm, non-randomized phase I-II escalation trial in 3 to 6 pts/cohorts. The treatment schedule was: M 50 mg/m2 (or 60, depending on dose level assignment) on day 1, T 30 mg/m2 on day 2 and 9, H 4 mg/kg on day 2 followed by weekly dose of 2 mg/kg, every three weeks. MTD dose was identified on the basis of DLT defined according to WHO grade classification of toxicity or specific conditions of LVEF decrease. A pharmacokinetic (PK) analysis of doxorubicin until 72 hours after M administration was planned. Results: Seven pts, median age 63 yrs, were enrolled. Four pts were allocated to dose level 50/30 (M/T) and other 3 pts to dose level 60/30. At the dose level 60/30 febrile neutropenia (DLT) occurred in 2 pts. Other 2 pts experienced febrile neutropenia (no DLT). One event of tachicardia (WHO grade 1) at maximum tolerated dose level was completely recovered without treatment. LVEF values were unmodified. Six patients were enrolled in the PK analysis. T pharmacokinetic data obtained on day 2 and on day 9 were not statistically different. Conclusions: The MTD was defined at M 50 mg/m2 in combination with T 30 mg/m2. The cardiac tolerability was good, with no significant change in LVEF values from baseline to the end of therapy. PK data indicated that the residual concentration of M found on day 2 was did not influence T pharmacokinetics, according to literature data. A phase II study is ongoing to assess activity and PK interactions between drugs. Till now 25 patients have been enrolled, the planned sample size is 45. No significant financial relationships to disclose.

Phase I trial combining SCH 66336 to temozolomide (TMZ) for patients with grade 3 or 4 malignant gliomas (MG)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13004-e13004
Author(s):  
A. Desjardins ◽  
D. A. Reardon ◽  
S. Gururangan ◽  
K. Peters ◽  
S. Threatt ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Cellular Proliferation ◽  
Malignant Gliomas ◽  
Maximum Tolerated Dose ◽  
Radiographic Evaluation ◽  
Farnesyl Transferase ◽  
Primary Endpoints ◽  
Elevated Creatinine ◽  
Grade 3

e13004 Background: Ras plays a crucial role in the control of cellular proliferation and differentiation. Farnesylation is an essential step in the post-translational processing of Ras. SCH 66336 inhibits farnesyl transferase, the crucial enzyme in this process. We report a phase I trial of TMZ and SCH 66336. Methods: Eligibility included: adult patients with stable or recurrent MG (GBM, anaplastic astrocytoma [AA], anaplastic oligodendroglioma [AO]) previously treated with radiation therapy (RT) and with or without chemotherapy; interval of at least two weeks between prior RT, or four weeks between prior chemotherapy; Karnofsky ≥ 60%; and adequate hematologic, renal and liver function. Patients were divided in two strata: those receiving enzyme-inducing antiepileptic drugs (EIAED) and those not receiving EIAED. Each patient was treated with TMZ for five days every 28 days, first cycle dosed at 150 mg/m2 and subsequent cycles at 200 mg/m2. SCH 66336 was dosed orally daily and was dose escalated. Responses were assessed after two cycles (8 weeks). The primary endpoints of this study were to determine the maximum tolerated dose (MTD) of SCH 66336 when administered with TMZ, and the toxicity of this combination. Results: Thirty-six patients were enrolled (25 GBM, 6 AA, 3 AO). Fifteen patients have been accrued to the EIAED stratum at SCH 66336 doses of 125, 175, and 250 mg orally BID. Twenty-one patients have been accrued to the non-EIAED stratum at SCH 66336 doses of 75, 100, 150, and 200 mg orally BID. Dose-limiting toxicities were: deep venous thrombosis (1 grade 3); nausea and vomiting (1 grade 3); diarrhea (1 grade 3); elevated ALT (1 grade 3); elevated creatinine (1 grade 3); and fatigue (1 grade 3). Radiographic evaluation reported: 2 partial responses, 14 stable disease for at least 4 cycles, and 11 disease progression after either the first or second cycle. Sixteen patients have completed at least six cycles. One patient is still on treatment, completing cycle 12. The MTD of this combination for the EIAED stratum is 175 mg BID and the non-EIAED stratum is 150 mg BID. Conclusions: SCH 66336 in combination with TMZ is well-tolerated and shows promising response when administered to patient when stable on TMZ alone or after RT and TMZ. No significant financial relationships to disclose.

scholarly journals An Exploration of Trifluridine/Tipiracil in Combination with Irinotecan in Patients with Pretreated Advanced Gastric Cancer

2021 ◽  
Author(s):  
Takuro Mizukami ◽  
Keiko Minashi ◽  
Hiroki Hara ◽  
Tomohiro Nishina ◽  
Yusuke Amanuma ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3 ◽  
Recommended Phase Ii Dose

Abstract Background: Trifluridine/tipiracil (FTD/TPI) and irinotecan are treatment options for heavily pretreated patients with advanced gastric cancer but with limited efficacies. We investigated the combination of FTD/TPI and irinotecan for such patients.Methods: Patients who refractory to fluoropyrimidine, platinum and taxane were enrolled into four cohorts (Level 1A/1B/2A/2B) used an escalated dose of irinotecan [100 (Level 1) or 125 mg/m2 (Level 2) on days 1 and 15] with 2 schedules of FTD/TPI 35 mg/m2/dose: twice daily, on days 1-5 and 8-12 (Level A) or on days 1-5 and days 15-19 (Level B) of a 28-day cycle. The primary and secondary objectives were determination of maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D) , and evaluation of disease control rate (DCR), respectively. Results: Eleven patients were enrolled; 2 at Level 1A, 3 at Level 1B and 6 at Level 2B. DLTs occurred in 2/2 patient at Level 1A, and 2/6 patients at Level 2B. Grade 3 or higher treatment-related adverse events were neutropenia (90.9%), leukopenia (54.5%), anemia (45.5%) and febrile neutropenia (18.2%). One patient at Level 2B achieved partial response and the DCR was 72.7% (95% CI 39.0- 94.0%). The median progression-free survival and overall survival was 3.0 months (95% CI 0.92- not reached) and 10.2 months (95% CI 2.2- not reached), respectively.Conclusion: The RP2D of FTD/TPI combined with irinotecan was determined to be Level 1B with manageable hematologic toxicities and feasible non-hematologic toxicities. Further evaluation for its efficacy in the RP2D is necessary. Mini-abstract: A phases Ib study of trifluridine/tipiracil in combination with irinotecan for advanced gastric cancer determined the recommended dose with manageable hematologic toxicities and feasible non-hematologic toxicities.

Phase II study of bevacizumab plus irinotecan and carboplatin for recurrent WHO grade 3 malignant gliomas with no prior bevacizumab failure.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2095-2095
Author(s):  
Annick Desjardins ◽  
James J Vredenburgh ◽  
Katherine B. Peters ◽  
Stevie Threatt ◽  
James Emmett Herndon ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Malignant Gliomas ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Who Grade ◽  
Adequate Organ Function ◽  
Grade 3 ◽  
Reversible Encephalopathy ◽  
Anti Tumor Activity

2095^ Background: No standard treatment exists for recurrent WHO grade 3 malignant glioma patients. Bevacizumab (BV) with irinotecan has significant anti-tumor activity for recurrent glioblastoma. Carboplatin has anti-glioma activity and can potentiate the cytotoxicity of irinotecan. We evaluated the progression-free survival (PFS) of BV in combination to irinotecan and carboplatin in recurrent WHO grade 3 malignant gliomas, as well as its safety. Methods: Adult patients with measurable recurrent WHO grade 3 malignant glioma, ≥12 weeks after radiation therapy, ≥4 weeks after chemotherapy, with adequate organ function, KPS ≥70%, no prior failure or grade ≥3 toxicity to the agents, and no contraindications to BV were eligible for study. Patients received BV at 10 mg/kg with irinotecan on days 1 and 15 of a 28-day cycle. The dose of irinotecan was 125 mg/m2 for patients not on enzyme inducing anti-epileptics (EIAEDs) and 340 mg/m2 for patients on EIAEDs. All patients received carboplatin at an AUC of 4 on day 1 of each cycle. MRIs were obtained every 8 weeks. Results: As planned, 39 WHO grade III malignant glioma patients were enrolled on study. Median age was 47 (range, 26-71). At a median follow up of 14 months, the 6-month PFS is 69% and the median PFS is 11 months. A median of 8 cycles were given. Seven patients completed the planned course of treatment (12 cycles) with hypometabolic PET scan and nine patients remain on study. Fifteen patients came off study due to disease progression and eight due to toxicity. As of 1/25/2012, 22 patients are still alive and 17 have died. Grade 3-4 toxicities included: neutropenia (grade 3, n=12; grade 4, n= 1), thrombocytopenia (grade 3, n=6; grade 4, n=4), nausea (grade 3, n=7), diarrhea (grade 3, n=2), deep venous thrombosis (grade 3, n=2), febrile neutropenia (grade 3, n=1; grade 4, n=1), fatigue (grade 3, n=8; grade 4, n=1), cerebral infarction (grade 4, n=3), intracranial hemorrhage (grade 4, n=1), posterior reversible encephalopathy syndrome (grade 3, n=1). Conclusions: The combination of bevacizumab, irinotecan and carboplatin for WHO grade 3 malignant glioma patients is effective and with no more than expected toxicity.

Final report: A phase I trial of BYL719 in combination with gemcitabine and nab-paclitaxel in locally advanced and metastatic pancreatic cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 398-398
Author(s):  
Heloisa P. Soares ◽  
Taymeyah E. Al-Toubah ◽  
Richard D. Kim ◽  
Jongphil Kim ◽  
Neron K Lewis ◽  
...  
Keyword(s):  
Phase I ◽  
Phase 1 ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Therapeutic Window ◽  
Final Report ◽  
Gene Encoding ◽  
Grade 3

398 Background: The PI3K/mTOR pathway has emerged as a potential target for anticancer therapy. Considerable evidence suggests that targeting a single isoform of PI3K (p110α) would have sufficient antitumor activity and improved therapeutic window. Further, PI3KCA mutations, gene encoding isoform p110α, are described in pancreatic adenocarcinoma (PAC). BYL719 is an oral class I α-specific PI3K inhibitor that showed preclinical anti-tumor activity. The first in human phase 1 trial of BYL719 defined the maximum tolerated dose (MTD) at 400mg QD. Methods: This was a phase I, single center study (standard 3+3 design). The primary objective was to determine the MTD of BYL719 in combination with gemcitabine (G) and nab-paclitaxel (nabP) as frontline therapy in locally advanced or metastatic PAC. BYL719 was given orally daily (Table). Patients (pts) were restaged q2 cycles. The study was closed prematurely due to slow accrual. Results: Fifteen pts were enrolled (median age was 58 years). Three pts each participated in cohorts 1 and 2. Nine pts were enrolled in cohort 3, but 4 were replaced (3 pts withdrew consent prior to evaluation and 1 missed > 10 days of treatment). One pt in cohort 3 had DLT related to grade 3 nausea and vomiting. A total of 19 grade 3 and 4 adverse events were records as probably or possibly associated with BYL719. The most common ones were hyperglycemia, anemia, and neutrophil count decreased. One pt developed Posterior reversible encephalopathy syndrome (PRES) during cycle 7. Although we could not completely exclude BYL719 as a cause, PRES was attributed to G. One pt had sudden death during cycle 4 that was attributed to progression. Only 8 pts were evaluable for response. Two had stable disease, 5 had partial responses and 1 had progression. The median progression-free survival and overall survival were 5.36 months (1.6 to 10 months) and 8.74 months (3.8 to 21.2 months) respectively. Conclusions: The combination of full doses of G + nabP and BYL719 can be safely administered up to BYL dose of 250 mg/day. Clinical trial information: NCT02155088. [Table: see text]

Phase I study of tramatinib combined with sorafenib in patients (pts) with advanced hepatocellular cancer (HCC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 431-431 ◽  
Author(s):  
Emilie Wang ◽  
Dae Won Kim ◽  
Amit Mahipal ◽  
Dung-Tsa Chen ◽  
Biwei Cao ◽  
...  
Keyword(s):  
Phase I ◽  
Mapk Pathway ◽  
Hepatocellular Cancer ◽  
Study Drug ◽  
Progression Free Survival ◽  
Mek Inhibitor ◽  
Maximum Tolerated Dose ◽  
Mapk Signaling ◽  
Advanced Hcc ◽  
Grade 3

431 Background: RAS/RAF/MEK/ERK (MAPK) signaling pathway is associated with proliferation, progression, and survival of HCC. Preclinical data suggests that activation of MAPK pathway may be one of resistant mechanisms of sorafenib, and the combination of MEK inhibitor and sorafenib can induce synergistic anticancer activity in HCC. We evaluated the safety and efficacy of trametinib (MEK inhibitor) combined with sorafenib in HCC. Methods: This was a phase I single center study with standard 3+3 design for pts with treatment naïve advanced HCC. The primary endpoints are determining dose limiting toxicities (DLT) and maximum tolerated dose (MTD). Secondary endpoints include overall survival (OS), progression free survival (PFS), and disease control rate (DCR). Initial plan was to enroll pts in 4 escalating dose levels (dl)—trametinib 1mg daily (qd)/sorafenib 200mg twice daily (bid)(dl 1), trametinib 1.5mg qd/sorafenib 200mg bid (dl 2), trametinib 1.5mg qd/sorafenib 400mg bid (dl 3), trametinib 2mg qd/sorafenib 400mg bid (dl 4). Eligible pts had advanced unresectable HCC, ECOG PS 1, Child-Pugh Score 6, and adequate organ function. Results: 17 pts were treated in 3 different dl of trametinib and sorafenib (3 in dl 1, 8 in dl 2, and 6 in dl 3). Median age was 65 years (range 40-80) with 64.7% male. All pts were evaluated for toxicity, but only 15 were evaluable for DLT. 2 pts were replaced as they came off of study within 1 month (1 pt in dl 3 due to varices unrelated to the study drug, 1 pt in dl 2 for voluntary withdrawal due to side effects). DLT was noted in dl 3 with 2 pts (grade 4 hypertension (HTN) and grade 3 elevated (elev) of bilirubin/AST/ALT > 7 days). Most common grade 3/4 treatment related adverse events were elev AST (47.1%), HTN (23.5%), elev Alk Phos (17.6%), elev ALT (5.9%), elev bilirubin (5.9%), and diarrhea (5.9%). The median PFS was 4.0 months (mo), and median OS was 5.8 mo. 11 pts were evaluable for response after cycle 2 (8 stable disease (SD), 2 disease progression (PD), 1 partial response). 3 pts were evaluable for response after cycle 4 (1 SD, 2 PD). DCR was 63.6%. Conclusions: Trametinib and sorafenib can be safely administered up to trametinib 1.5mg qd and sorafenib 200mg bid for pts with advanced HCC. Clinical trial information: NCT02292173.

A phase I trial of intratumoral (i.t.) administration of reovirus in patients with histologically confirmed recurrent malignant gliomas (MGs)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1563-1563 ◽  
Author(s):  
P. A. Forsyth ◽  
G. Roldan ◽  
D. George ◽  
C. Wallace ◽  
D. G. Morris ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Malignant Gliomas ◽  
Maximum Tolerated Dose ◽  
Ras Signaling ◽  
In Vivo Models ◽  
Viral Shedding ◽  
Grade 3 ◽  
Dose Levels

1563 Background: Reovirus is an oncolytic virus which replicates preferentially in transformed cells possessing activated Ras signaling pathways. Promising activity was found in in vivo models of MGs and in a phase I trial in patients (pts.) with cutaneous metastases from systemic cancer. We performed this dose-escalation trial of i.t. administration of reovirus to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) in pts. with recurrent MG. Response, survival and time to progression (TTP) were secondary aims. Methods: Pts. were ≥ 18 yrs old, had a KPS ≥ 60, received prior radiotherapy ± chemotherapy, a histologically proven recurrence of MG and recurred ≤ 3 times. Reovirus was administered i.t. stereotactically at one of three dose levels (1 × 107, 1 × 108 or 1 × 109 TCID50) in a volume of 0.9 mls. Results: Twelve pts. were treated at 3 dose levels; seven were men, the median (mdn) KPS was 80, mdn age was 53.5 yrs, 10 had glioblastoma multiforme, one anaplastic astrocytoma and another anaplastic oligoastrocytoma. There were the 1st, 2nd or 3rd recurrences in 6, 5 and 1 pts., respectively. During i.t. viral administration all pts. were treated with prophylactic anticonvulsants and 6 (50%) were receiving corticosteroids. The 1st, 2nd and 3rd cohorts contained 3, 6 and 3 pts., respectively. There were no grade 3 or 4 adverse events definitely or probably related to the administration of reovirus. A transient increase in GGT was possibly related to reovirus administration and a patient experienced grade 3 motor weakness that could be related to post-injection edema. Viral shedding and systemic immune responses were examined but results are pending. There were no CR, or PR; a pt. had SD, 10 PD and one was not evaluable. The mdn survival was 20 weeks (range, 6–171), 6 pts. survived > 6 months and 3 are alive 6, 7 and 40 months from the reovirus injection. The mdn TTP was 4.3 weeks (range: 3.4–39). Conclusions: A MTD was not reached. The intratumoral administration or reovirus was well tolerated in patients with recurrent MGs. Phase 2 studies in MGs are planned. [Table: see text]

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